{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:12:07Z","timestamp":1773306727340,"version":"3.50.1"},"reference-count":196,"publisher":"Acoustical Society of America (ASA)","issue":"5","content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,11,1]]},"abstract":"<jats:p>Currently, no approved medicines are available for the prevention or treatment of hearing loss. Pharmaceutical industry productivity across all therapeutic indications has historically been disappointing, with a 90% chance of failure in delivering a marketed drug after entering clinical evaluation. To address these failings, initiatives have been applied in the three cornerstones of medicine discovery: target selection, clinical candidate selection, and clinical studies. These changes aimed to enable data-informed decisions on the translation of preclinical observations into a safe, clinically effective medicine by ensuring the best biological target is selected, the most appropriate chemical entity is advanced, and that the clinical studies enroll the correct patients. The specific underlying pathologies need to be known to allow appropriate patient selection, so improved diagnostics are required, as are methodologies for measuring in the inner ear target engagement, drug delivery and pharmacokinetics. The different therapeutic strategies of protecting hearing or preventing hearing loss versus restoring hearing are reviewed along with potential treatments for tinnitus. Examples of current investigational drugs are discussed to highlight key challenges in drug discovery and the learnings being applied to improve the probability of success of launching a marketed medicine.<\/jats:p>","DOI":"10.1121\/1.5132706","type":"journal-article","created":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T16:30:59Z","timestamp":1574872259000},"page":"3652-3667","update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Medicines discovery for auditory disorders: Challenges for industry"],"prefix":"10.1121","volume":"146","author":[{"given":"Rick P. C.","family":"Cousins","sequence":"first","affiliation":[{"name":"University College London Ear Institute, University College London , London, WC1X 8EE, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"231","published-online":{"date-parts":[[2019,11,27]]},"reference":[{"key":"2023080122073490400_c1","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.drudis.2016.11.021","article-title":"Global vision of druggability issues: Applications and perspectives","volume":"22","year":"2017","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c2","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1007\/s10162-017-0634-8","article-title":"Emerging gene therapies for genetic hearing loss","volume":"18","year":"2017","journal-title":"J. Assoc. Res. Otolaryngol. JARO"},{"key":"2023080122073490400_c3","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1039\/C6MD00341A","article-title":"From haystack to needle: Finding value with DNA encoded library technology at GSK","volume":"7","year":"2016","journal-title":"Med. Chem. Commun."},{"key":"2023080122073490400_c4","doi-asserted-by":"publisher","first-page":"17348","DOI":"10.1038\/s41598-018-35587-x","article-title":"DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory organ of Corti","volume":"8","year":"2018","journal-title":"Sci Rep"},{"key":"2023080122073490400_c5","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1016\/S0140-6736(13)60142-7","article-title":"Tinnitus","volume":"382","year":"2013","journal-title":"Lancet"},{"key":"2023080122073490400_c6","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1159\/000218207","article-title":"Repair of the vestibular system via adenovector delivery of Atoh1: A potential treatment for balance disorders","volume":"66","year":"2009","journal-title":"Adv. Otorhinolaryngol."},{"key":"2023080122073490400_c7","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1002\/ar.22594","article-title":"Low dose oxidative stress induces mitochondrial damage in hair cells","volume":"295","year":"2012","journal-title":"Anat. Rec. (Hoboken)"},{"key":"2023080122073490400_c8","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1016\/j.drudis.2016.07.007","article-title":"Quality guidelines for oral drug candidates: Dose, solubility and lipophilicity","volume":"21","year":"2016","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c9","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1126\/science.284.5421.1837","article-title":"Math1: An essential gene for the generation of inner ear hair cells","volume":"284","year":"1999","journal-title":"Science (New York, N.Y.)"},{"key":"2023080122073490400_c10","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1080\/00016480601110188","article-title":"Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration","volume":"127","year":"2007","journal-title":"Acta Otolaryngol."},{"key":"2023080122073490400_c11","doi-asserted-by":"crossref","first-page":"531","DOI":"10.29200\/acsmedchemrev-v52","article-title":"To market, to market\u20132016","volume-title":"2017 Medicinal Chemistry Reviews","author":"Bronson","year":"2017"},{"key":"2023080122073490400_c12","doi-asserted-by":"publisher","first-page":"eaal1670","DOI":"10.1126\/scisignal.aal1670","article-title":"Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists","volume":"10","year":"2017","journal-title":"Sci Signal"},{"key":"2023080122073490400_c13","doi-asserted-by":"publisher","first-page":"a033217","DOI":"10.1101\/cshperspect.a033217","article-title":"Age-related hearing loss","volume":"9","year":"2019","journal-title":"Cold Spring Harb Perspect Med."},{"key":"2023080122073490400_c14","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.heares.2019.02.016","article-title":"The search for noise-induced cochlear synaptopathy in humans: Mission impossible?","volume":"377","year":"2019","journal-title":"Hear. Res."},{"key":"2023080122073490400_c15","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1039\/C7MD00633K","article-title":"Approaches to target tractability assessment\u2014A practical perspective","volume":"9","year":"2018","journal-title":"Med. Chem. Commun."},{"key":"2023080122073490400_c16","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/j.cmet.2014.11.003","article-title":"Activation of SIRT3 by the NAD(+) precursor nicotinamide riboside protects from noise-induced hearing loss","volume":"20","year":"2014","journal-title":"Cell Metab."},{"key":"2023080122073490400_c17","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nchembio.1197","article-title":"Target validation using chemical probes","volume":"9","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"2023080122073490400_c18","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nchembio.1813","article-title":"Know your target, know your molecule","volume":"11","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"2023080122073490400_c19","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.cmet.2016.05.006","article-title":"CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism","volume":"23","year":"2016","journal-title":"Cell Metab."},{"key":"2023080122073490400_c20","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.drudis.2017.10.007","article-title":"Medicinal chemistry in drug discovery in big pharma: Past, present and future","volume":"23","year":"2018","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c21","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.5059\/yukigoseikyokaishi.75.1171","article-title":"Constrained peptides in drug discovery and development","volume":"75","year":"2017","journal-title":"J. Synth. Organic Chem. Jpn."},{"key":"2023080122073490400_c22","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1080\/17460441.2017.1365056","article-title":"Ligand efficiency metrics in drug discovery: The pros and cons from a practical perspective","volume":"12","year":"2017","journal-title":"Exp. Opin. Drug Discov."},{"key":"2023080122073490400_c23","doi-asserted-by":"publisher","first-page":"17496","DOI":"10.1038\/s41598-017-17406-x","article-title":"Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage","volume":"7","year":"2017","journal-title":"Sci. Rep."},{"key":"2023080122073490400_c24","doi-asserted-by":"publisher","first-page":"e1004688","DOI":"10.1371\/journal.pgen.1004688","article-title":"Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss","volume":"10","year":"2014","journal-title":"PLoS Genet."},{"key":"2023080122073490400_c25","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.mce.2016.11.003","article-title":"NAD and the aging process: Role in life, death and everything in between","volume":"455","year":"2017","journal-title":"Mol. Cell Endocrinol."},{"key":"2023080122073490400_c26","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1021\/acs.jmedchem.7b00932","article-title":"Phenotypic optimization of urea-thiophene carboxamides to yield potent, well tolerated, and orally active protective agents against aminoglycoside-induced hearing loss","volume":"61","year":"2018","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c27","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1021\/acs.jmedchem.7b01272","article-title":"Protac-induced protein degradation in drug discovery: Breaking the rules or just making new ones?","volume":"61","year":"2018","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c28","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1002\/jcph.1008","article-title":"Repeated-dose oral N-acetylcysteine in Parkinson's disease: Pharmacokinetics and effect on brain glutathione and oxidative stress","volume":"58","year":"2018","journal-title":"J. Clin. Pharmacol."},{"key":"2023080122073490400_c29","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1021\/acs.jmedchem.6b00098","article-title":"Epigenetics: Novel therapeutics targeting epigenetics","volume":"59","year":"2016","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c30","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrd4309","article-title":"Lessons learned from the fate of AstraZeneca's drug pipeline: A five-dimensional framework","volume":"13","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c31","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.semcdb.2016.10.003","article-title":"Atoh1 in sensory hair cell development: Constraints and cofactors","volume":"65","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"2023080122073490400_c32","first-page":"1","article-title":"Ion channel drug discovery: A historical perspective","volume":"39","year":"2015","journal-title":"Ion Channel Drug Discov."},{"key":"2023080122073490400_c33","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1002\/lary.24834","article-title":"Steroids for treatment of sudden sensorineural hearing loss: A meta-analysis of randomized controlled trials","volume":"125","year":"2015","journal-title":"Laryngoscope"},{"key":"2023080122073490400_c34","unstructured":"CSDD (2013). \u201c Causes of clinical failures vary widely by therapeutic class, phase of study. Tufts CSDD study assessed compounds entering clinical testing in 2000\u201309,\u201d Tufts CSDD Impact Report 15, Tufts University, Medford, MA."},{"key":"2023080122073490400_c35","doi-asserted-by":"publisher","first-page":"a020412","DOI":"10.1101\/cshperspect.a020412","article-title":"The blood-brain barrier","volume":"7","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2023080122073490400_c36","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1021\/acs.jmedchem.7b00717","article-title":"Beyond the rule of 5: Lessons learned from AbbVie's drugs and compound collection","volume":"61","year":"2018","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c37","doi-asserted-by":"publisher","first-page":"e79","DOI":"10.2196\/resprot.9095","article-title":"The physiological bases of hidden noise-induced hearing loss: Protocol for a functional neuroimaging study","volume":"7","year":"2018","journal-title":"JMIR Res. Protoc."},{"key":"2023080122073490400_c38","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1021\/jm301297f","article-title":"Demystifying brain penetration in central nervous system drug discovery","volume":"56","year":"2013","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c39","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1001\/jamaoncol.2016.2214","article-title":"Genomics- and transcriptomics-based patient selection for cancer treatment with immune checkpoint inhibitors: A review","volume":"2","year":"2016","journal-title":"JAMA Oncol."},{"key":"2023080122073490400_c40","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/clpt.2009.295","article-title":"Trends in risks associated with new drug development: Success rates for investigational drugs","volume":"87","year":"2010","journal-title":"Clin. Pharmacol. Ther."},{"key":"2023080122073490400_c41","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.jhealeco.2016.01.012","article-title":"Innovation in the pharmaceutical industry: New estimates of R&D costs","volume":"47","year":"2016","journal-title":"J. Health Econ."},{"key":"2023080122073490400_c42","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/clpt.2013.117","article-title":"Clinical approval success rates for investigational cancer drugs","volume":"94","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"2023080122073490400_c43","doi-asserted-by":"publisher","first-page":"159","DOI":"10.5688\/ajpe778159","article-title":"Fail fast","volume":"77","year":"2013","journal-title":"Am. J. Pharm. Educ."},{"key":"2023080122073490400_c44","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1080\/17460441.2017.1264385","article-title":"Drug discovery beyond the rule of 5\u2014Opportunities and challenges","volume":"12","year":"2017","journal-title":"Exp. Opin. Drug Discov."},{"key":"2023080122073490400_c45","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/j.chembiol.2014.08.013","article-title":"Oral druggable space beyond the rule of 5: Insights from drugs and clinical candidates","volume":"21","year":"2014","journal-title":"Chem. Biol."},{"key":"2023080122073490400_c46","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.semcdb.2016.11.002","article-title":"Insights into inner ear-specific gene regulation: Epigenetics and non-coding RNAs in inner ear development and regeneration","volume":"65","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"2023080122073490400_c47","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.drudis.2016.01.003","article-title":"Translational medicine guide transforms drug development processes: The recent Merck experience","volume":"21","year":"2016","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c48","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1001\/jamaneurol.2014.4524","article-title":"Novel methods and technologies for 21st-century clinical trials: A review","volume":"72","year":"2015","journal-title":"JAMA Neurol."},{"key":"2023080122073490400_c49","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.neuron.2010.10.011","article-title":"Hearing impairment: A panoply of genes and functions","volume":"68","year":"2010","journal-title":"Neuron"},{"key":"2023080122073490400_c50","first-page":"73","article-title":"(+)-Azasetron for use in the treatment of ear disorders","year":"2017"},{"key":"2023080122073490400_c51","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3389\/fnagi.2016.00265","article-title":"Can animal models contribute to understanding tinnitus heterogeneity in humans?","volume":"8","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"2023080122073490400_c52","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1210\/js.2017-00092","article-title":"Targeting NAD+ in metabolic disease: New insights into an old molecule","volume":"1","year":"2017","journal-title":"J. Endocr. Soc."},{"key":"2023080122073490400_c53","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1093\/hmg\/ddn402","article-title":"GRM7 variants confer susceptibility to age-related hearing impairment","volume":"18","year":"2009","journal-title":"J. Hum. Mol. Genet."},{"key":"2023080122073490400_c54","doi-asserted-by":"publisher","first-page":"S24","DOI":"10.1016\/j.drudis.2011.12.008","article-title":"What makes a good drug target?","volume":"17","year":"2012","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c55","doi-asserted-by":"publisher","first-page":"961","DOI":"10.4155\/tde.15.32","article-title":"Molecular determinants of blood\u2013brain barrier permeation","volume":"6","year":"2015","journal-title":"Therap. Deliv."},{"key":"2023080122073490400_c56","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1021\/acschemneuro.6b00273","article-title":"Technically extended multiparameter optimization (TEMPO): An advanced robust scoring scheme to calculate central nervous system druggability and monitor lead optimization","volume":"8","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"2023080122073490400_c57","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.heares.2018.06.017","article-title":"Anatomical basis of drug delivery to the inner ear","volume":"368","year":"2018","journal-title":"Hear. Res."},{"key":"2023080122073490400_c58","doi-asserted-by":"publisher","DOI":"10.15761\/NDT.1000117","article-title":"The role of mitochondrial oxidative stress in hearing loss","volume":"1","year":"2017","journal-title":"Neurol. Disord. Therap."},{"key":"2023080122073490400_c59","first-page":"341","article-title":"Ion channel drug discovery: Future perspectives","volume":"39","year":"2015","journal-title":"Ion Channel Drug Discov."},{"key":"2023080122073490400_c60","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1097\/JCP.0000000000000536","article-title":"Derisking psychiatric drug development: The NIMH's fast fail program, a novel precompetitive model","volume":"36","year":"2016","journal-title":"J. Clin. Psychopharmacol."},{"key":"2023080122073490400_c61","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.heares.2016.12.002","article-title":"Tinnitus with a normal audiogram: Relation to noise exposure but no evidence for cochlear synaptopathy","volume":"344","year":"2017","journal-title":"Hear. Res."},{"key":"2023080122073490400_c62","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.heares.2018.03.008","article-title":"Impaired speech perception in noise with a normal audiogram: No evidence for cochlear synaptopathy and no relation to lifetime noise exposure","volume":"364","year":"2018","journal-title":"Hear. Res."},{"key":"2023080122073490400_c63","first-page":"2331216517736689","article-title":"Designing clinical trials for assessing the effectiveness of interventions for tinnitus","volume":"21","year":"2017","journal-title":"Trends Hear."},{"key":"2023080122073490400_c64","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/nrd.2016.184","article-title":"Phase II and phase III failures: 2013\u20132015","volume":"15","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c65","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/nbt.2786","article-title":"Clinical development success rates for investigational drugs","volume":"32","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"2023080122073490400_c66","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.heares.2016.12.010","article-title":"Translational issues in cochlear synaptopathy","volume":"349","year":"2017","journal-title":"Hear. Res."},{"key":"2023080122073490400_c67","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.bmcl.2018.12.001","article-title":"Advances in lead generation","volume":"29","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2023080122073490400_c68","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/nrd892","article-title":"The druggable genome","volume":"1","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c69","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/S1359-6446(04)03069-7","article-title":"Ligand efficiency: A useful metric for lead selection","volume":"9","year":"2004","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c70","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nrd4163","article-title":"The role of ligand efficiency metrics in drug discovery","volume":"13","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c71","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/nrd.2016.164","article-title":"Trial watch: Impact of genetically supported target selection on R&D productivity","volume":"15","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c72","doi-asserted-by":"publisher","first-page":"121","DOI":"10.3389\/fphar.2016.00121","article-title":"Therapeutic approaches to genetic ion channelopathies and perspectives in drug discover","volume":"7","year":"2016","journal-title":"Front. Pharmacol."},{"key":"2023080122073490400_c73","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1038\/nrd2132","article-title":"Drugs, their targets and the nature and number of drug targets","volume":"5","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c74","doi-asserted-by":"publisher","first-page":"28964","DOI":"10.1038\/srep28964","article-title":"S1PR2 variants associated with auditory function in humans and endocochlear potential decline in mouse","volume":"6","year":"2016","journal-title":"Sci. Rep."},{"key":"2023080122073490400_c75","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1097\/MAO.0000000000002116","article-title":"Objective measures of tinnitus: A systematic review","volume":"40","year":"2019","journal-title":"Otol. Neurotol."},{"key":"2023080122073490400_c76","first-page":"11","article-title":"New drug approvals hit an all-time high FDA gave its green light to 59 new molecular entities in 2018","volume":"97","year":"2019","journal-title":"Chem. Eng. News"},{"key":"2023080122073490400_c77","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.nbd.2016.08.004","article-title":"Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm","volume":"97","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"2023080122073490400_c78","doi-asserted-by":"publisher","first-page":"8829","DOI":"10.1523\/JNEUROSCI.5176-14.2015","article-title":"Potent KCNQ2\/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus","volume":"35","year":"2015","journal-title":"J. Neurosci."},{"key":"2023080122073490400_c79","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1124\/jpet.112.200915","article-title":"ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: In vitro and in vivo characterization","volume":"344","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2023080122073490400_c80","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13321-019-0330-2","article-title":"The nature of ligand efficiency","volume":"11","year":"2019","journal-title":"J. Cheminform."},{"key":"2023080122073490400_c81","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1038\/nrd4793","article-title":"Two decades of new drug development for central nervous system disorders","volume":"14","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c82","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/S0140-6736(17)31791-9","article-title":"Safety and efficacy of Ebselen for the prevention of noise-induced hearing loss: A randomised, double-blind, placebo-controlled, phase 2 trial","volume":"390","year":"2017","journal-title":"Lancet"},{"key":"2023080122073490400_c83","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.heares.2006.08.006","article-title":"Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase","volume":"226","year":"2007","journal-title":"Hear. Res."},{"key":"2023080122073490400_c84","doi-asserted-by":"publisher","first-page":"150","DOI":"10.14336\/AD.2014.0500150","article-title":"NAD(+) metabolism in age-related hearing loss","volume":"5","year":"2014","journal-title":"Aging Dis."},{"key":"2023080122073490400_c85","doi-asserted-by":"publisher","first-page":"e1292","DOI":"10.1038\/cddis.2014.255","article-title":"Augmentation of NAD(+) by NQO1 attenuates cisplatin-mediated hearing impairment","volume":"5","year":"2014","journal-title":"Cell Death Dis."},{"key":"2023080122073490400_c86","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.heares.2015.04.002","article-title":"Nicotinamide adenine dinucleotide: An essential factor in preserving hearing in cisplatin-induced ototoxicity","volume":"326","year":"2015","journal-title":"Hear. Res."},{"key":"2023080122073490400_c87","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.1002\/cmdc.201300344","article-title":"Small-molecule modulators for epigenetics targets","volume":"8","year":"2013","journal-title":"Chem. Med. Chem."},{"key":"2023080122073490400_c88","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.csbj.2016.09.002","article-title":"The promises of quantitative systems pharmacology modelling for drug development","volume":"14","year":"2016","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"2023080122073490400_c89","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.heares.2016.12.008","article-title":"Noise-induced cochlear synaptopathy: Past findings and future studies","volume":"349","year":"2017","journal-title":"Hear. Res."},{"key":"2023080122073490400_c90","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.heares.2015.01.002","article-title":"Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: A randomized clinical trial","volume":"323","year":"2015","journal-title":"Hear. Res."},{"key":"2023080122073490400_c91","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.heares.2015.02.009","article-title":"Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss","volume":"330","year":"2015","journal-title":"Hear. Res."},{"key":"2023080122073490400_c92","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.heares.2019.03.003","article-title":"Translating animal models to human therapeutics in noise-induced and age-related hearing loss","volume":"377","year":"2019","journal-title":"Hear. Res."},{"key":"2023080122073490400_c93","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.heares.2016.11.013","article-title":"Cellular mechanisms of noise-induced hearing loss","volume":"349","year":"2017","journal-title":"Hear. Res."},{"key":"2023080122073490400_c94","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/nbt.3781","article-title":"A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear","volume":"35","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"2023080122073490400_c95","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1146\/annurev-pharmtox-010818-021556","article-title":"Therapeutic approaches to the treatment of tinnitus","volume":"59","year":"2019","journal-title":"Ann. Rev. Pharmacol. Toxicol."},{"key":"2023080122073490400_c96","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/978-3-319-13473-4","article-title":"Strategies for evaluating antioxidant efficacy in clinical trials assessing prevention of noise-induced hearing loss","volume-title":"Free Radicals in ENT Pathology, Oxidative Stress in Applied Basic Research and Clinical Practice","author":"Miller","year":"2015"},{"key":"2023080122073490400_c97","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.heares.2006.10.006","article-title":"Mechanisms of noise-induced hearing loss indicate multiple methods of prevention","volume":"226","year":"2007","journal-title":"Hear. Res."},{"key":"2023080122073490400_c98","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.addr.2016.01.018","article-title":"Molecular inflation, attrition and the rule of five","volume":"101","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"2023080122073490400_c99","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1021\/acsmedchemlett.5b00157","article-title":"Molecular property design: Does everyone get it?","volume":"6","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"2023080122073490400_c100","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.tins.2018.01.008","article-title":"Why do hearing aids fail to restore normal auditory perception?","volume":"41","year":"2018","journal-title":"Trends Neurosci."},{"key":"2023080122073490400_c101","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12920-018-0395-1","article-title":"Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes","volume":"11","year":"2018","journal-title":"BMC Med. Genom."},{"key":"2023080122073490400_c102","first-page":"1","article-title":"Ears wide open","volume-title":"BioCentury","year":"2017"},{"key":"2023080122073490400_c103","doi-asserted-by":"publisher","first-page":"9980","DOI":"10.1073\/pnas.1302770110","article-title":"Pathogenic plasticity of Kv7.2\/3 channel activity is essential for the induction of tinnitus","volume":"110","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2023080122073490400_c104","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.heares.2017.01.003","article-title":"Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms","volume":"349","year":"2017","journal-title":"Hear. Res."},{"key":"2023080122073490400_c105","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1080\/13607863.2014.915924","article-title":"Hearing loss and dementia\u2014Who is listening?","volume":"18","year":"2014","journal-title":"Aging Ment. Health"},{"key":"2023080122073490400_c106","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1037\/a0024238","article-title":"Hearing loss and cognition in the Baltimore longitudinal study of aging","volume":"25","year":"2011","journal-title":"Neuropsychology"},{"key":"2023080122073490400_c107","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.addr.2016.04.029","article-title":"Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions","volume":"101","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"2023080122073490400_c108","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"2023080122073490400_c109","doi-asserted-by":"publisher","first-page":"2673","DOI":"10.1016\/S0140-6736(17)31363-6","article-title":"Dementia prevention, intervention, and care","volume":"390","year":"2017","journal-title":"Lancet"},{"key":"2023080122073490400_c110","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrd4024","article-title":"Small-molecule modulation of neurotrophin receptors: A strategy for the treatment of neurological disease","volume":"12","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c111","doi-asserted-by":"publisher","first-page":"377","DOI":"10.3389\/fnins.2016.00377","article-title":"Genetics of tinnitus: An emerging area for molecular diagnosis and drug development","volume":"10","year":"2016","journal-title":"Front. Neurosci."},{"key":"2023080122073490400_c112","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.neuroscience.2014.05.057","article-title":"Metabotropic glutamate receptors in auditory processing","volume":"274","year":"2014","journal-title":"Neuroscience"},{"key":"2023080122073490400_c113","doi-asserted-by":"publisher","first-page":"e77153","DOI":"10.1371\/journal.pone.0077153","article-title":"Association of GRM7 variants with different phenotype patterns of age-related hearing impairment in an elderly male Han Chinese population","volume":"8","year":"2013","journal-title":"PLoS One"},{"key":"2023080122073490400_c114","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.heares.2018.05.005","article-title":"Diseases and targets for local drug delivery to the inner ear","volume":"368","year":"2018","journal-title":"Hear. Res."},{"key":"2023080122073490400_c115","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1097\/00001813-200506000-00013","article-title":"Combined oral delivery of Ebselen and allopurinol reduces multiple cisplatin toxicities in rat breast and ovarian cancer models while enhancing anti-tumor activity","volume":"16","year":"2005","journal-title":"Anti-Cancer Drugs"},{"key":"2023080122073490400_c116","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-3-319-40848-4","article-title":"Development of drugs for noise-induced hearing loss","volume-title":"Translational Research in Audiology, Neurotology, and the Hearing Sciences. Springer Handbook of Auditory Research","author":"Le Prell","year":"2016"},{"key":"2023080122073490400_c117","first-page":"110","article-title":"Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea","volume":"9","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"2023080122073490400_c118","doi-asserted-by":"publisher","first-page":"R878","DOI":"10.1016\/j.cub.2014.06.053","article-title":"Cochlear implants","volume":"24","year":"2014","journal-title":"Curr. Biol."},{"key":"2023080122073490400_c119","doi-asserted-by":"publisher","first-page":"16081","DOI":"10.1038\/ncomms16081","article-title":"Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening","volume":"8","year":"2017","journal-title":"Nat. Commun."},{"key":"2023080122073490400_c120","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD011795","article-title":"Interventions for tinnitus in adults: An overview of systematic reviews","year":"2015","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"2023080122073490400_c121","doi-asserted-by":"publisher","first-page":"eaal3175","DOI":"10.1126\/scitranslmed.aal3175","article-title":"Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans","volume":"10","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"2023080122073490400_c122","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1007\/s12253-018-0388-6","article-title":"Age-related hearing impairment associated NAT2, GRM7, GRHL2 susceptibility gene polymorphisms and haplotypes in Roma and Hungarian populations","volume":"25","year":"2018","journal-title":"Pathol. Oncol. Res."},{"key":"2023080122073490400_c123","doi-asserted-by":"publisher","first-page":"360","DOI":"10.3109\/14992027.2013.769066","article-title":"Why do people fitted with hearing aids not wear them?","volume":"52","year":"2013","journal-title":"Int. J. Audiol."},{"key":"2023080122073490400_c124","doi-asserted-by":"publisher","first-page":"120","DOI":"10.3389\/fncel.2018.00120","article-title":"Spontaneous hair cell regeneration is prevented by increased notch signaling in supporting cells","volume":"12","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"2023080122073490400_c125","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1016\/j.celrep.2017.01.066","article-title":"Clonal expansion of Lgr5-positive cells from mammalian cochlea and high-purity generation of sensory hair cells","volume":"18","year":"2017","journal-title":"Cell Rep."},{"key":"2023080122073490400_c126","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1002\/jnr.20267","article-title":"Calcineurin activation contributes to noise-induced hearing loss","volume":"78","year":"2004","journal-title":"J. Neurosci. Res."},{"key":"2023080122073490400_c127","doi-asserted-by":"publisher","first-page":"236","DOI":"10.3389\/fnmol.2017.00236","article-title":"Recent advancements in the regeneration of auditory hair cells and hearing restoration","volume":"10","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"2023080122073490400_c128","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.neuron.2012.10.032","article-title":"Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma","volume":"77","year":"2013","journal-title":"Neuron"},{"key":"2023080122073490400_c129","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/nrd.2017.244","article-title":"Impact of a five-dimensional framework on R&D productivity at AstraZeneca","volume":"17","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c130","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.drudis.2011.12.020","article-title":"Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival","volume":"17","year":"2012","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c131","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1517\/13543784.2015.960076","article-title":"Early investigational drugs for hearing loss","volume":"24","year":"2015","journal-title":"Exp. Opin. Investig. Drugs"},{"key":"2023080122073490400_c132","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/nrd.2018.16","article-title":"Pfizer exits neuroscience","volume":"17","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c133","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/nrd4533","article-title":"New treatment options for hearing loss","volume":"14","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c134","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1021\/ml500146d","article-title":"Validity of ligand efficiency metrics","volume":"5","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"2023080122073490400_c135","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1002\/ddr.21461","article-title":"Dose translation between laboratory animals and human in preclinical and clinical phases of drug development","volume":"79","year":"2018","journal-title":"Drug Dev. Res."},{"key":"2023080122073490400_c136","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1038\/ng.3314","article-title":"The support of human genetic evidence for approved drug indications","volume":"47","year":"2015","journal-title":"Nat. Genet."},{"key":"2023080122073490400_c137","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.heares.2012.08.016","article-title":"GRM7 variants associated with age-related hearing loss based on auditory perception","volume":"294","year":"2012","journal-title":"Hear. Res."},{"key":"2023080122073490400_c138","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1017\/S1041610216001459","article-title":"Age-related hearing loss in older adults with cognitive impairment","volume":"29","year":"2017","journal-title":"Int. Psychogeriatr."},{"key":"2023080122073490400_c139","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.brainres.2009.02.079","article-title":"Mechanisms and genes in human strial presbycusis from animal models","volume":"1277","year":"2009","journal-title":"Brain Res."},{"key":"2023080122073490400_c140","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1038\/nrd2199","article-title":"How many drug targets are there?","volume":"5","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c141","doi-asserted-by":"publisher","first-page":"e1000020","DOI":"10.1371\/journal.pgen.1000020","article-title":"Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death","volume":"4","year":"2008","journal-title":"PLoS Genet."},{"key":"2023080122073490400_c142","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1086\/378900","article-title":"Are we there yet?\u201d: Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits","volume":"73","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"2023080122073490400_c143","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1097\/MAO.0000000000002088","article-title":"SENS-401 effectively reduces severe acoustic trauma-induced hearing loss in male rats with twice daily administration delayed up to 96 hours","volume":"40","year":"2019","journal-title":"Otol. Neurotol."},{"key":"2023080122073490400_c144","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1097\/MAO.0000000000001546","article-title":"Oral administration of clinical stage drug candidate SENS-401 effectively reduces cisplatin-induced hearing loss in rats","volume":"38","year":"2017","journal-title":"Otol. Neurotol."},{"key":"2023080122073490400_c145","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.heares.2014.09.009","article-title":"Importance of cochlear health for implant function","volume":"322","year":"2015","journal-title":"Hear. Res."},{"key":"2023080122073490400_c146","doi-asserted-by":"publisher","first-page":"CD008514","DOI":"10.1002\/14651858.CD008514.pub2","article-title":"Intratympanic steroids for Meniere's disease or syndrome","year":"2011","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"2023080122073490400_c147","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nrd4051","article-title":"Validating therapeutic targets through human genetics","volume":"12","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c148","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c149","doi-asserted-by":"publisher","first-page":"12331","DOI":"10.1523\/JNEUROSCI.0096-15.2015","article-title":"Temporary neurotrophin treatment prevents deafness-induced auditory nerve degeneration and preserves function","volume":"35","year":"2015","journal-title":"J. Neurosci."},{"key":"2023080122073490400_c150","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1111\/j.1749-6632.2010.05868.x","article-title":"Hearing loss: A common disorder caused by many rare alleles","volume":"1214","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2023080122073490400_c151","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1517\/14712598.2015.1009889","article-title":"Atoh1 gene therapy in the cochlea for hair cell regeneration","volume":"15","year":"2015","journal-title":"Exp. Opin. Biol. Ther."},{"key":"2023080122073490400_c152","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1016\/j.drudis.2018.05.028","article-title":"Understanding drug targets: No such thing as bad news","volume":"23","year":"2018","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c153","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/978-3-642-45106-5","article-title":"Modulation of neurotrophin signaling by monoclonal antibodies","volume":"220","year":"2014","journal-title":"Handb. Exp. Pharmacol."},{"key":"2023080122073490400_c154","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/nrg1432","article-title":"Pharmacogenetics and drug development: The path to safer and more effective drugs","volume":"5","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"2023080122073490400_c155","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1016\/S1359-6446(05)03666-4","article-title":"The druggable genome: An update","volume":"10","year":"2005","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c156","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1124\/dmd.115.065920","article-title":"Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: A systematic review of published models, applications, and model verification","volume":"43","year":"2015","journal-title":"Drug Metab. Dispos."},{"key":"2023080122073490400_c157","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.expneurol.2010.05.013","article-title":"TrkB and TrkC agonist antibodies improve function, electrophysiologic and pathologic features in Trembler J mice","volume":"224","year":"2010","journal-title":"Exp. Neurol."},{"key":"2023080122073490400_c158","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.heares.2017.12.010","article-title":"Communication pathways to and from the inner ear and their contributions to drug delivery","volume":"362","year":"2018","journal-title":"Hear. Res."},{"key":"2023080122073490400_c159","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.heares.2018.03.002","article-title":"Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications","volume":"368","year":"2018","journal-title":"Hear. Res."},{"key":"2023080122073490400_c160","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c161","doi-asserted-by":"publisher","first-page":"2807","DOI":"10.1016\/j.bmc.2018.03.008","article-title":"Macrocyclic \u03b1 helical peptide therapeutic modality: A perspective of learnings and challenges","volume":"26","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"2023080122073490400_c162","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.heares.2013.12.004","article-title":"Tinnitus in men, mice (as well as other rodents), and machines","volume":"311","year":"2014","journal-title":"Hear. Res."},{"key":"2023080122073490400_c163","doi-asserted-by":"publisher","first-page":"13452","DOI":"10.1523\/JNEUROSCI.2156-11.2011","article-title":"Tinnitus with a normal audiogram: Physiological evidence for hidden hearing loss and computational model","volume":"31","year":"2011","journal-title":"J. Neurosci."},{"key":"2023080122073490400_c164","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1097\/MAO.0000000000001689","article-title":"Biological therapies of the inner ear: What otologists need to consider","volume":"39","year":"2018","journal-title":"Otol. Neurotol."},{"key":"2023080122073490400_c165","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1097\/MAO.0000000000002194","article-title":"Hearing protection, restoration, and regeneration: An overview of emerging therapeutics for inner ear and central hearing disorders","volume":"40","year":"2019","journal-title":"Otol. Neurotol."},{"key":"2023080122073490400_c166","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/00034894931020S101","article-title":"Cochlear pathology in presbycusis","volume":"102","year":"1993","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"2023080122073490400_c167","doi-asserted-by":"publisher","first-page":"3006","DOI":"10.1016\/j.bmc.2018.04.004","article-title":"Practical application of ligand efficiency metrics in lead optimization","volume":"26","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"2023080122073490400_c168","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1080\/13543784.2017.1269171","article-title":"Emerging therapeutic interventions against noise-induced hearing loss","volume":"26","year":"2017","journal-title":"Exp. Opin. Investig. Drugs"},{"key":"2023080122073490400_c169","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1021\/acs.jmedchem.8b00686","article-title":"Two decades under the influence of the rule of five and the changing properties of approved oral drugs","volume":"62","year":"2018","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c170","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.jcyt.2017.04.008","article-title":"Regenerative medicine in hearing recovery","volume":"19","year":"2017","journal-title":"Cytotherapy"},{"key":"2023080122073490400_c171","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1097\/MOP.0000000000000410","article-title":"Navigating genetic diagnostics in patients with hearing loss","volume":"28","year":"2016","journal-title":"Curr. Opin. Pediatr."},{"key":"2023080122073490400_c172","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/nrd.2016.85","article-title":"Trends in clinical success rates","volume":"15","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023080122073490400_c173","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1159\/000275062","article-title":"Current trends in treating hearing loss in elderly people: A review of the technology and treatment options\u2014A mini-review","volume":"56","year":"2010","journal-title":"Gerontology"},{"key":"2023080122073490400_c174","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/978-3-319-40848-4","article-title":"Developing a molecular therapeutic for hearing loss","volume-title":"Translational Research in Audiology, Neurotology, and the Hearing Sciences. Springer Handbook of Auditory Research","author":"Le Prell","year":"2016"},{"key":"2023080122073490400_c175","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1242\/dev.137976","article-title":"Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea","volume":"143","year":"2016","journal-title":"Development (Cambridge, England)"},{"key":"2023080122073490400_c176","doi-asserted-by":"publisher","first-page":"24907","DOI":"10.1038\/srep24907","article-title":"Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure","volume":"6","year":"2016","journal-title":"Sci. Rep."},{"key":"2023080122073490400_c177","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1124\/jpet.107.124701","article-title":"In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists","volume":"323","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2023080122073490400_c178","unstructured":"Thomas, D. W. J. B., Audette, J., Carroll, A., Dow-Hygelund, C., and Hay, M. (2016). \u201c Clinical development success rates 2006\u20132015,\u201d BIO Industry Analysis, https:\/\/www.bio.org\/sites\/default\/files\/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf (Last viewed February 2019)."},{"key":"2023080122073490400_c179","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1002\/lio2.65","article-title":"Hearing loss as a risk factor for dementia: A systematic review","volume":"2","year":"2017","journal-title":"Laryngosc. Investig. Otolaryngol."},{"key":"2023080122073490400_c180","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.heares.2005.06.010","article-title":"Protective effect of calcineurin inhibitors on acoustic injury of the cochlea","volume":"209","year":"2005","journal-title":"Hear. Res."},{"key":"2023080122073490400_c181","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/BF00463612","article-title":"Stria vascularis in acoustic trauma","volume":"237","year":"1983","journal-title":"Arch. Otorhinolaryngol."},{"key":"2023080122073490400_c182","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.jddst.2017.03.003","article-title":"Nanoparticle drug delivery systems for inner ear therapy: An overview","volume":"39","year":"2017","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"2023080122073490400_c183","doi-asserted-by":"publisher","first-page":"10294","DOI":"10.1002\/anie.201611914","article-title":"New modalities for challenging targets in drug discovery","volume":"56","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"2023080122073490400_c184","doi-asserted-by":"publisher","first-page":"9004","DOI":"10.1021\/acs.jmedchem.8b00378","article-title":"New modalities, technologies, and partnerships in probe and lead generation: Enabling a mode-of-action centric paradigm","volume":"61","year":"2018","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c185","doi-asserted-by":"publisher","first-page":"3570","DOI":"10.1200\/JCO.2016.68.4217","article-title":"Industry-academic relationship in a new era of drug discovery","volume":"34","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"2023080122073490400_c186","doi-asserted-by":"publisher","first-page":"7264","DOI":"10.1158\/1078-0432.CCR-07-2184","article-title":"The challenge of drugging undruggable targets in cancer: Lessons learned from targeting BCL-2 family members","volume":"13","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"2023080122073490400_c187","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.mcp.2015.03.008","article-title":"Non-syndromic hearing loss gene identification: A brief history and glimpse into the future","volume":"29","year":"2015","journal-title":"Mol. Cell Probes"},{"key":"2023080122073490400_c188","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1016\/j.drudis.2018.02.015","article-title":"Quantitative metrics for drug-target ligandability","volume":"23","year":"2018","journal-title":"Drug Discov. Today"},{"key":"2023080122073490400_c189","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1021\/acschemneuro.6b00029","article-title":"Central nervous system multiparameter optimization desirability: Application in drug discovery","volume":"7","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"2023080122073490400_c190","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003998.pub3","article-title":"Steroids for idiopathic sudden sensorineural hearing loss","year":"2013","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"2023080122073490400_c191","doi-asserted-by":"publisher","first-page":"568","DOI":"10.3760\/cma.j.issn.1001-9391.2014.08.002","article-title":"Association between GPX-1 single nucleotide polymorphisms and susceptibility to noise-induced hearing loss among Chinese Han population","volume":"32","year":"2014","journal-title":"Zhonghua Laodong Weisheng Zhiyebing Zazhi"},{"key":"2023080122073490400_c192","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1016\/S0140-6736(17)31073-5","article-title":"Global hearing health care: New findings and perspectives","volume":"390","year":"2017","journal-title":"Lancet"},{"key":"2023080122073490400_c193","doi-asserted-by":"publisher","first-page":"6421","DOI":"10.1021\/acs.jmedchem.8b00180","article-title":"Mapping the efficiency and physicochemical trajectories of successful optimizations","volume":"61","year":"2018","journal-title":"J. Med. Chem."},{"key":"2023080122073490400_c194","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12881-017-0515-3","article-title":"Effect of GRM7 polymorphisms on the development of noise-induced hearing loss in Chinese Han workers: A nested case-control study","volume":"19","year":"2018","journal-title":"BMC Med. Genet."},{"key":"2023080122073490400_c195","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1109\/TBME.2017.2718939","article-title":"Challenges in improving cochlear implant performance and accessibility","volume":"64","year":"2017","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"2023080122073490400_c196","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1007\/s00405-016-4401-y","article-title":"A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus","volume":"274","year":"2017","journal-title":"Eur. Arch. Otorhinolaryngol."}],"container-title":["The Journal of the Acoustical Society of America"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.aip.org\/asa\/jasa\/article-pdf\/146\/5\/3652\/18069713\/3652_1_1.5132706.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.aip.org\/asa\/jasa\/article-pdf\/146\/5\/3652\/18069713\/3652_1_1.5132706.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,27]],"date-time":"2024-07-27T20:31:34Z","timestamp":1722112294000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.aip.org\/jasa\/article\/146\/5\/3652\/994809\/Medicines-discovery-for-auditory-disorders"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,1]]},"references-count":196,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,11,1]]}},"URL":"https:\/\/doi.org\/10.1121\/1.5132706","relation":{},"ISSN":["0001-4966"],"issn-type":[{"value":"0001-4966","type":"print"}],"subject":[],"published-other":{"date-parts":[[2019,11]]},"published":{"date-parts":[[2019,11,1]]}}}