{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:39:50Z","timestamp":1789810790859,"version":"4.0.1"},"reference-count":100,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2026,11]]},"DOI":"10.1016\/j.ejmech.2026.119082","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T15:05:25Z","timestamp":1781967925000},"page":"119082","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Discovery and optimization of diarylsulfone-based dual M3-Antagonists and \u03b22-Agonists (MABAs) as inhaled bronchodilators"],"prefix":"10.1016","volume":"317","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9385-5560","authenticated-orcid":false,"given":"Mariana Celestina","family":"Frojuello Costa Bernstorff Dami\u00e3o","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando Henrique de","family":"Souza Gama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Marcos Antonio","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno Vinicius Motta","family":"Teodoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano R.W.","family":"Guimar\u00e3es","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Mascarello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9233-0696","authenticated-orcid":false,"given":"Hatylas","family":"Azevedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"5","key":"10.1016\/j.ejmech.2026.119082_bib1","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1111\/j.1365-2125.2012.04467.x","article-title":"Sir David Jack: An Extraordinary Drug Discoverer and Developer","volume":"75","author":"Page","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.119082_bib2","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1515\/chem-2020-0056","article-title":"Chirality of \u03b22-agonists. An Overview of Pharmacological Activity, Stereoselective Analysis, and Synthesis","volume":"18","author":"Ru\u017eena","year":"2020","journal-title":"Open Chem."},{"key":"10.1016\/j.ejmech.2026.119082_bib3","series-title":"Beta2-agonists. StatPearls","author":"Hsu","year":"2025"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib4","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.pupt.2012.05.007","article-title":"cAMP Regulation of Airway Smooth Muscle Function","volume":"26","author":"Billington","year":"2013","journal-title":"Pulm. Pharmacol. Ther."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1124\/pr.119.018150","article-title":"Pharmacology and Therapeutics of Bronchodilators Revisited","volume":"72","author":"Matera","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"10.1016\/j.ejmech.2026.119082_bib6","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/978-3-642-23274-9_14","article-title":"Muscarinic Receptor Antagonists: Effects on Pulmonary Function","volume":"208","author":"Buels","year":"2012","journal-title":"Handb. Exp. Pharmacol."},{"issue":"7","key":"10.1016\/j.ejmech.2026.119082_bib7","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/nrd4295","article-title":"Muscarinic Acetylcholine Receptors: Novel Opportunities for Drug Development","volume":"13","author":"Kruse","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1177\/2040622313518227","article-title":"Long-acting Muscarinic Receptor Antagonists for the Treatment of Chronic Airway Diseases","volume":"5","author":"Alagha","year":"2014","journal-title":"Ther. Adv. Chronic Dis."},{"issue":"12","key":"10.1016\/j.ejmech.2026.119082_bib9","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.rmed.2004.05.003","article-title":"The Functional Impact of Adding Salmeterol and Tiotropium in Patients with Stable COPD","volume":"98","author":"Cazzola","year":"2004","journal-title":"Respir. Med."},{"issue":"13","key":"10.1016\/j.ejmech.2026.119082_bib10","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.4155\/fmc.11.106","article-title":"Dual-Pharmacology Muscarinic Antagonist and \u03b22 Agonist Molecules for the Treatment of Chronic Obstructive Pulmonary Disease","volume":"3","author":"Hughes","year":"2011","journal-title":"Future Med. Chem."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119082_bib11","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.jaci.2020.06.014","article-title":"The Latest on the Role of LAMAs in Asthma","volume":"146","author":"Cazzola","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"issue":"22","key":"10.1016\/j.ejmech.2026.119082_bib12","doi-asserted-by":"crossref","first-page":"6623","DOI":"10.3390\/jcm11226623","article-title":"LABA\/LAMA as First-Line Therapy for COPD: A Summary of the Evidence and Guideline Recommendations","volume":"11","author":"Miravitlles","year":"2022","journal-title":"J. Clin. Med."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119082_bib13","first-page":"364","article-title":"Update on Asthma Management Guidelines","volume":"121","author":"Dubin","year":"2024","journal-title":"Mo. Med."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib14","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/all.16436","article-title":"The Bronchodilator and Anti-Inflammatory Effect of Long-Acting Muscarinic Antagonists in Asthma: An EAACI Position Paper","volume":"80","author":"Agache","year":"2025","journal-title":"Allergy"},{"key":"10.1016\/j.ejmech.2026.119082_bib15","doi-asserted-by":"crossref","first-page":"745","DOI":"10.2147\/COPD.S404690","article-title":"GOLD 2023 Update: Implications for Clinical Practice","volume":"18","author":"Tamondong-Lachica","year":"2023","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119082_bib16","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1124\/pr.111.004580","article-title":"Pharmacology and Therapeutics of Bronchodilators","volume":"64","author":"Cazzola","year":"2012","journal-title":"Pharmacol. Rev."},{"issue":"15","key":"10.1016\/j.ejmech.2026.119082_bib17","doi-asserted-by":"crossref","first-page":"10233","DOI":"10.1021\/acs.jmedchem.2c00609","article-title":"Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and \u03b22 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases","volume":"65","author":"Carzaniga","year":"2022","journal-title":"J. Med. Chem."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib18","doi-asserted-by":"crossref","DOI":"10.1183\/13993003.00700-2023","article-title":"Revisiting Asthma Pharmacotherapy: Where Do We Stand and Where Do We Want to Go?","volume":"62","author":"Cazzola","year":"2023","journal-title":"Eur. Respir. J."},{"key":"10.1016\/j.ejmech.2026.119082_bib19","doi-asserted-by":"crossref","DOI":"10.1016\/j.bmcl.2021.127975","article-title":"Discovery of a Novel Class of Inhaled Dual Pharmacology Muscarinic Antagonist and \u03b22 Agonist (MABA) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)","volume":"41","author":"Rancati","year":"2021","journal-title":"Bioorg. Med. Chem. Lett"},{"issue":"3","key":"10.1016\/j.ejmech.2026.119082_bib20","first-page":"163","article-title":"Clinical Safety of Long-Acting \u03b22-Agonist and Inhaled Corticosteroid Combination Therapy in COPD","volume":"3","author":"Decramer","year":"2006","journal-title":"COPD J. Chronic Obstr. Pulm. Dis."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s12890-020-1153-7","article-title":"A Randomized, Controlled, Repeat-dose Study of Batefenterol\/Fluticasone Furoate Compared with Placebo in the Treatment of COPD","volume":"20","author":"Crim","year":"2020","journal-title":"BMC Pulm. Med."},{"issue":"Suppl 1","key":"10.1016\/j.ejmech.2026.119082_bib22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s12931-020-01470-5","volume":"21","author":"Jimenez","year":"2020","journal-title":"Respir. Res."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119082_bib23","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1021\/jm501915g","volume":"58","author":"Hughes","year":"2015","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119082_bib24","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.arbres.2021.06.005","article-title":"The Future of Bronchodilators in COPD and Asthma","volume":"58","author":"Cazzola","year":"2022","journal-title":"Arch. Bronconeumol."},{"issue":"4","key":"10.1016\/j.ejmech.2026.119082_bib25","doi-asserted-by":"crossref","DOI":"10.1183\/13993003.00972-2021","article-title":"The Novel Bronchodilator Navafenterol: a Phase 2a, Multicentre, Randomised, Double-blind, Placebo-controlled Crossover Trial in COPD","volume":"59","author":"Singh","year":"2022","journal-title":"Eur. Respir. J."},{"key":"10.1016\/j.ejmech.2026.119082_bib26","article-title":"AstraZeneca deals another blow to IL-12, dumping therapy to follow BMS, Merck KGaA out of race","author":"Taylor","year":"2023","journal-title":"Fierce Biotech"},{"key":"10.1016\/j.ejmech.2026.119082_bib27","doi-asserted-by":"crossref","first-page":"615","DOI":"10.2147\/COPD.S190603","article-title":"Randomized Dose-finding Study of Batefenterol via Dry Powder Inhaler in Patients with COPD","volume":"14","author":"Crim","year":"2019","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"10.1016\/j.ejmech.2026.119082_bib28","doi-asserted-by":"crossref","first-page":"559","DOI":"10.2147\/JEP.S259330","article-title":"Long-Acting Muscarinic Antagonists Under Investigational to Treat Chronic Obstructive Pulmonary Disease","volume":"12","author":"Ora","year":"2020","journal-title":"J. Exp. Pharmacol."},{"issue":"Suppl 61","key":"10.1016\/j.ejmech.2026.119082_bib29","article-title":"A Randomized Placebo Controlled Trial of AZD8999 (LAS190792) a Novel Dual Acting Bronchodilator in Asthmatics","volume":"50","author":"Astbury","year":"2017","journal-title":"Eur. Respir. J."},{"key":"10.1016\/j.ejmech.2026.119082_bib30","article-title":"CHF 6366: A Novel Dual Potent Bronchodilator with Antimuscarinic and Beta-2 Agonist Activity \u2013 Results from the First-in-Human Healthy Male Volunteers Trial","volume":"203","author":"Kots","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"issue":"12","key":"10.1016\/j.ejmech.2026.119082_bib31","doi-asserted-by":"crossref","first-page":"9816","DOI":"10.1021\/acs.jmedchem.4c00298","article-title":"Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and \u03b22 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases","volume":"67","author":"Carzaniga","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119082_bib32","doi-asserted-by":"crossref","first-page":"425","DOI":"10.2147\/COPD.S49179","article-title":"Role of Indacaterol and the Newer Very Long-acting \u03b22-Agonists in Patients with Stable COPD: a Review","volume":"8","author":"Ridolo","year":"2013","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"issue":"9","key":"10.1016\/j.ejmech.2026.119082_bib33","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1021\/jm100068m","article-title":"The Identification of Indacaterol as an Ultralong-Acting Inhaled \u03b22-Adrenoceptor Agonist","volume":"53","author":"Baur","year":"2010","journal-title":"J. Med. Chem."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119082_bib34","doi-asserted-by":"crossref","DOI":"10.1002\/prp2.70154","article-title":"A Comparison of the Molecular Pharmacological Properties of Current Short, Long, and Ultra-long-acting \u03b22-Agonists Used for Asthma and COPD","volume":"13","author":"Proudman","year":"2025","journal-title":"Pharmacol. Res. Perspect."},{"issue":"11","key":"10.1016\/j.ejmech.2026.119082_bib35","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1038\/s41589-018-0145-x","article-title":"Structural Insights into Binding Specificity, Efficacy and Bias of a \u03b22AR Partial Agonist","volume":"14","author":"Masureel","year":"2018","journal-title":"Nat. Chem. Biol."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119082_bib36","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1021\/acs.biochem.8b01237","article-title":"Structural Basis of Partial Agonism at the \u03b22-Adrenergic Receptor","volume":"58","author":"Shukla","year":"2019","journal-title":"Biochemistry"},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib37","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.bmc.2003.11.005","article-title":"Muscarinic M2 Antagonists: Anthranilamide Derivatives with Exceptional Selectivity and In Vivo Activity","volume":"12","author":"Clader","year":"2004","journal-title":"Bioorg. Med. Chem."},{"issue":"20","key":"10.1016\/j.ejmech.2026.119082_bib38","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1016\/S0960-894X(00)00438-8","article-title":"Diphenyl Sulfoxides as Selective Antagonists of the Muscarinic M2 Receptor","volume":"10","author":"Kozlowski","year":"2000","journal-title":"Bioorg. Med. Chem. Lett"},{"key":"10.1016\/j.ejmech.2026.119082_bib39","series-title":"Muscarinic Receptors","first-page":"3","article-title":"Overview of muscarinic receptor subtypes","author":"Eglen","year":"2012"},{"issue":"5","key":"10.1016\/j.ejmech.2026.119082_bib40","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/S0960-894X(02)00023-9","article-title":"Substituted 2-(R)-Methyl Piperazines as Muscarinic M2 Selective Ligands","volume":"12","author":"Kozlowski","year":"2002","journal-title":"Bioorg. Med. Chem. Lett"},{"issue":"19","key":"10.1016\/j.ejmech.2026.119082_bib41","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1016\/S0960-894X(00)00437-6","article-title":"Diphenylsulfone Muscarinic Antagonists: Piperidine Derivatives with High M2 Selectivity and Improved Potency","volume":"10","author":"Billard","year":"2000","journal-title":"Bioorg. Med. Chem. Lett"},{"issue":"20","key":"10.1016\/j.ejmech.2026.119082_bib42","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1016\/S0960-894X(00)00457-1","article-title":"Design and Synthesis of Piperidinyl Piperidine Analogues as Potent and Selective M2 Muscarinic Receptor Antagonists","volume":"10","author":"Wang","year":"2000","journal-title":"Bioorg. Med. Chem. Lett"},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib43","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.jchromb.2003.10.058","article-title":"Validation and Application of a Liquid Chromatography\u2013Tandem Mass Spectrometric Method for the Determination of SCH 211803 in Rat and Monkey Plasma Using Automated 96-well Protein Precipitation","volume":"799","author":"Yang","year":"2004","journal-title":"J. Chromatogr., B: Anal. Technol. Biomed. Life Sci."},{"issue":"4","key":"10.1016\/j.ejmech.2026.119082_bib44","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1021\/acsmedchemlett.4c00592","article-title":"Design, Synthesis, and Evaluation of a New Fluorescent Ligand for the M2 Muscarinic Acetylcholine Receptor","volume":"16","author":"Szab\u00f3","year":"2025","journal-title":"ACS Med. Chem. Lett."},{"key":"10.1016\/j.ejmech.2026.119082_bib45","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nature10867","article-title":"Structure and Dynamics of the M3 Muscarinic Acetylcholine Receptor","volume":"482","author":"Kruse","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.ejmech.2026.119082_bib46","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.coph.2014.02.006","article-title":"Muscarinic Acetylcholine Receptor X-ray Structures: Potential Implications for Drug Development","volume":"16","author":"Kruse","year":"2014","journal-title":"Curr. Opin. Pharmacol."},{"issue":"16","key":"10.1016\/j.ejmech.2026.119082_bib47","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1111\/bph.14707","article-title":"Second M3 Muscarinic Receptor Binding Site Contributes to Bronchoprotection by Tiotropium","volume":"176","author":"Kistemaker","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.119082_bib48","series-title":"Muscarinic Antagonists. US 6 043 255 A","author":"Lowe","year":"2000"},{"issue":"28","key":"10.1016\/j.ejmech.2026.119082_bib49","doi-asserted-by":"crossref","first-page":"4955","DOI":"10.1016\/S0040-4039(00)73291-6","article-title":"An Efficient Method for the Oxidation of Sulfides to Sulfones","volume":"35","author":"Su","year":"1994","journal-title":"Tetrahedron Lett."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119082_bib50","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1021\/jo7021372","article-title":"Scalable Synthesis of the VEGF-R2 Kinase Inhibitor JNJ-17029259 Using Ultrasound-Mediated Addition of MeLi\u2212CeCl3 to a Nitrile","volume":"73","author":"Reuman","year":"2008","journal-title":"J. Org. Chem."},{"issue":"18","key":"10.1016\/j.ejmech.2026.119082_bib51","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1021\/ja00252a056","article-title":"Highly Enantioselective Borane Reduction of Ketones Catalyzed by Chiral Oxazaborolidines. Mechanism and Synthetic Implications","volume":"109","author":"Corey","year":"1987","journal-title":"J. Am. Chem. Soc."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib52","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1124\/jpet.109.152470","article-title":"Preclinical Evaluation of Long-Acting Muscarinic Antagonists: Comparison of Tiotropium and Investigational Drugs","volume":"330","author":"Casarosa","year":"2009","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib53","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1124\/jpet.109.151639","article-title":"Characterization of Aclidinium Bromide, a Novel Inhaled Muscarinic Antagonist, with Long Duration of Action and a Favorable Pharmacological Profile","volume":"331","author":"Gavald\u00e0","year":"2009","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib54","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1124\/jpet.112.202051","article-title":"Pharmacological Characterization of GSK573719 (Umeclidinium): A Novel, Long-Acting, Inhaled Antagonist of the Muscarinic Cholinergic Receptors for Treatment of Pulmonary Diseases","volume":"345","author":"Salmon","year":"2013","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"7","key":"10.1016\/j.ejmech.2026.119082_bib55","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1177\/1087057115581770","article-title":"Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4)","volume":"20","author":"Smith","year":"2015","journal-title":"J. Biomol. Screen"},{"issue":"47","key":"10.1016\/j.ejmech.2026.119082_bib56","doi-asserted-by":"crossref","first-page":"12046","DOI":"10.1073\/pnas.1813988115","article-title":"Structure-guided Development of Selective M3 Muscarinic Acetylcholine Receptor Antagonists","volume":"115","author":"Liu","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA."},{"issue":"4","key":"10.1016\/j.ejmech.2026.119082_bib57","doi-asserted-by":"crossref","first-page":"525","DOI":"10.3390\/ijms17040525","article-title":"Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?","volume":"17","author":"Ram\u00edrez","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.ejmech.2026.119082_bib58","doi-asserted-by":"crossref","first-page":"22","DOI":"10.2174\/1875397300903010022","article-title":"HTRF: A Technology Tailored for Drug Discovery\u2014A Review of Theoretical Aspects and Recent Applications","volume":"3","author":"Degorce","year":"2009","journal-title":"Curr. Chem. Genom."},{"key":"10.1016\/j.ejmech.2026.119082_bib59","series-title":"Eli Lilly & Company and the National Center for Advancing Translational Sciences: Bethesda, MD","article-title":"Measurement of cAMP for G\u03b1s- and G\u03b1i protein-coupled receptors (GPCRs). Assay Guidance Manual [Online]","author":"Wang","year":"2004"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib60","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1021\/jo981316g","article-title":"Facile Preparation of Nucleoside-5\u2032-carboxylic Acids","volume":"64","author":"Epp","year":"1999","journal-title":"J. Org. Chem."},{"issue":"22","key":"10.1016\/j.ejmech.2026.119082_bib61","doi-asserted-by":"crossref","first-page":"23676","DOI":"10.1021\/acs.jmedchem.5c01911","article-title":"Expanding the Scope of PROTACs: Opportunities and Challenges in Topical Delivery","volume":"68","author":"Gioiello","year":"2025","journal-title":"J. Med. Chem."},{"issue":"7","key":"10.1016\/j.ejmech.2026.119082_bib62","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/S0040-4039(97)00088-9","article-title":"Enantio- and Diastereoselective Synthesis of All Four Stereoisomers of Formoterol","volume":"38","author":"Hett","year":"1997","journal-title":"Tetrahedron Lett."},{"issue":"13","key":"10.1016\/j.ejmech.2026.119082_bib63","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1016\/S0040-4039(98)00137-3","article-title":"Conformational Toolbox of Oxazaborolidine Catalysts in the Enantioselective Reduction of \u03b1-Bromo-ketone for the Synthesis of (R,R)-Formoterol","volume":"39","author":"Hett","year":"1998","journal-title":"Tetrahedron Lett."},{"key":"10.1016\/j.ejmech.2026.119082_bib64","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1055\/s-2000-8208","article-title":"A Practical Synthesis of tert-Alkylamines via the Ritter Reaction with Chloroacetonitrile","volume":"12","author":"Jirgensons","year":"2000","journal-title":"Synthesis"},{"issue":"6","key":"10.1016\/j.ejmech.2026.119082_bib65","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1177\/8755122518788809","article-title":"Drug Interactions with Oral Inhaled Medications","volume":"34","author":"Ajimura","year":"2018","journal-title":"J. Pharm. Technol."},{"issue":"11","key":"10.1016\/j.ejmech.2026.119082_bib66","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/crj.13073","article-title":"Fixed-dose Combination of Umeclidinium and Vilanterol for Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review","volume":"13","author":"Ramadan","year":"2019","journal-title":"Clin. Res. J."},{"issue":"17","key":"10.1016\/j.ejmech.2026.119082_bib67","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.2147\/COPD.S358927","article-title":"Association Between Inhaled \u03b22-agonists Initiation and Risk of Major Adverse Cardiovascular Events: A Population-based Nested Case-Control Study","volume":"2022","author":"Amegadzie","year":"2022","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib68","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1124\/jpet.118.255620","article-title":"Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist\/\u03b22-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile","volume":"370","author":"Aparici","year":"2019","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"8","key":"10.1016\/j.ejmech.2026.119082_bib69","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1002\/cpdd.616","article-title":"Pharmacokinetics, Excretion, and Mass Balance of [14C]-Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men","volume":"7","author":"Ambery","year":"2018","journal-title":"Clin. Pharmacol. Drug Dev."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119082_bib70","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s40268-015-0104-x","article-title":"Population Pharmacokinetics and Pharmacodynamics of GSK961081 (Batefenterol), a Muscarinic Antagonist and \u03b22-Agonist, in Moderate-to-Severe COPD Patients: Substudy of a Randomized Trial","volume":"15","author":"Ambery","year":"2015","journal-title":"Drugs R&D"},{"issue":"4","key":"10.1016\/j.ejmech.2026.119082_bib71","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1183\/09031936.00165712","article-title":"A New Class of Bronchodilator Improves Lung Function in COPD: A Trial With GSK961081","volume":"42","author":"Wielders","year":"2013","journal-title":"Eur. Respir. J."},{"issue":"12","key":"10.1016\/j.ejmech.2026.119082_bib72","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1124\/dmd.120.000103","article-title":"Revefenacin Absorption, Metabolism, and Excretion in Healthy Subjects and Pharmacological Activity of Its Major Metabolite","volume":"48","author":"Bourdet","year":"2020","journal-title":"Drug Metab. Dispos."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib73","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s12931-017-0647-1","article-title":"A 28-day, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of Nebulized Revefenacin in Patients with Chronic Obstructive Pulmonary Disease","volume":"18","author":"Pudi","year":"2017","journal-title":"Respir. Res."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib74","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/cpdd.732","article-title":"a Long-Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo- and Positive-Controlled Thorough QT Study","volume":"9","author":"Borin","year":"2020","journal-title":"Clin. Pharmacol. Drug Dev."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib75","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pupt.2014.05.005","article-title":"The In Vitro and In Vivo Profile of Aclidinium Bromide in Comparison with Glycopyrronium Bromide","volume":"28","author":"Gavald\u00e0","year":"2014","journal-title":"Pulm. Pharmacol. Ther."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119082_bib76","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/sj.bjp.0706724","article-title":"Pharmacological Assessment of the Duration of Action of Glycopyrrolate vs Tiotropium and Ipratropium in Guinea-pig and Human Airways","volume":"148","author":"Villetti","year":"2006","journal-title":"Br. J. Pharmacol."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib77","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.vascn.2010.05.016","article-title":"Application of the Classical Einthoven Model of Bronchoconstriction to the Study of Inhaled Bronchodilators in Rodents","volume":"63","author":"McNamara","year":"2011","journal-title":"J. Pharmacol. Toxicol. Methods"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119082_bib78","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1124\/jpet.114.216861","article-title":"Pharmacologic Characterization of GSK-961081 (TD-5959), a First-in-Class Inhaled Bifunctional Bronchodilator Possessing Muscarinic Receptor Antagonist and \u03b22-Adrenoceptor Agonist Properties","volume":"351","author":"Hegde","year":"2014","journal-title":"J. Pharmacol. Exp. Therapeut."},{"key":"10.1016\/j.ejmech.2026.119082_bib79","doi-asserted-by":"crossref","DOI":"10.2196\/56848","article-title":"The Effect of Inhaled Beta-2 Agonists on Heart Rate in Patients with Asthma: Sensor-Based Observational Study","volume":"8","author":"Khusial","year":"2024","journal-title":"JMIR Cardio"},{"key":"10.1016\/j.ejmech.2026.119082_bib80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pupt.2017.07.003","article-title":"Pharmacological Preclinical Characterization of LAS190792, a Novel Inhaled Bifunctional Muscarinic Receptor Antagonist\/\u03b22-Adrenoceptor Agonist (MABA) Molecule","volume":"46","author":"Aparici","year":"2017","journal-title":"Pulm. Pharmacol. Ther."},{"issue":"Suppl 61","key":"10.1016\/j.ejmech.2026.119082_bib81","article-title":"In Vitro Pharmacological Characterization of the Novel Inhaled Bronchodilator CHF6366 Acting as Dual Muscarinic Antagonist\/\u03b22-Agonist (MABA)","volume":"50","author":"Pastore","year":"2017","journal-title":"Eur. Respir. J."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119082_bib82","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/cpdd.274","article-title":"Open-Label, Randomized, 6-Way Crossover, Single-Dose Study to Determine the Pharmacokinetics of Batefenterol (GSK961081) and Fluticasone Furoate When Administered Alone or in Combination","volume":"5","author":"Ambery","year":"2016","journal-title":"Clin. Pharmacol. Drug Dev."},{"issue":"Suppl 1","key":"10.1016\/j.ejmech.2026.119082_bib83","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/s12931-020-01474-1","article-title":"Navafenterol (AZD8871) in Healthy Volunteers: Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of this Novel Inhaled, Long-acting, Dual-pharmacology Bronchodilator, in Two Phase I, Randomised, Single-blind, Placebo-controlled Studies","volume":"21","author":"Balaguer","year":"2020","journal-title":"Respir. Res."},{"issue":"Suppl 1","key":"10.1016\/j.ejmech.2026.119082_bib84","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12931-020-01347-7","article-title":"Navafenterol (AZD8871) in Patients with COPD: A Randomized, Double-blind, Phase I Study Evaluating Safety and Pharmacodynamics of Single Doses of this Novel, Inhaled, Long-acting, Dual-pharmacology Bronchodilator","volume":"21","author":"Singh","year":"2020","journal-title":"Respir. Res."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib85","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1021\/jo00002a049","article-title":"A Practical Enantioselective Synthesis of \u03b1,\u03b1-Diaryl-2-pyrrolidinemethanol. Preparation and Chemistry of the Corresponding Oxazaborolidines","volume":"56","author":"Mathre","year":"1991","journal-title":"J. Org. Chem."},{"issue":"11","key":"10.1016\/j.ejmech.2026.119082_bib86","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1093\/bioinformatics\/btr168","article-title":"ProDy: Protein Dynamics Inferred from Theory and Experiments","volume":"27","author":"Bakan","year":"2011","journal-title":"Bioinformatics"},{"key":"10.1016\/j.ejmech.2026.119082_bib87","author":"Forli"},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib88","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1021\/acs.jctc.0c01006","article-title":"Accelerating AutoDock4 with GPUs and Gradient-Based Local Search","volume":"17","author":"Santos-Martins","year":"2021","journal-title":"J. Chem. Theor. Comput."},{"key":"10.1016\/j.ejmech.2026.119082_bib89","unstructured":"Center for Computational Structural Biology. AutoDock-GPU: AutoDock for GPUs and Other Accelerators. https:\/\/github.com\/ccsb-scripps\/AutoDock-GPU (accessed 2026-May-1)."},{"key":"10.1016\/j.ejmech.2026.119082_bib90","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/acsptsci.5c00452","article-title":"Comprehensive Analysis of Clinically Discontinued Compounds Using an In Vitro Secondary Pharmacology Panel to Predict Potential Safety Risks during Drug Development","volume":"8","author":"Albert","year":"2025","journal-title":"ACS Pharmacol. Transl. Sci."},{"issue":"22","key":"10.1016\/j.ejmech.2026.119082_bib91","doi-asserted-by":"crossref","first-page":"7920","DOI":"10.1073\/pnas.84.22.7920","article-title":"Cloning of the cDNA for the Human Beta 1-adrenergic Receptor","volume":"84","author":"Frielle","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119082_bib92","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/sj.bjp.0706048","article-title":"The Selectivity of \u03b2-Adrenoceptor Antagonists at the Human \u03b21, \u03b22 and \u03b23 Adrenoceptors","volume":"144","author":"Baker","year":"2005","journal-title":"Br. J. Pharmacol."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119082_bib93","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1177\/108705719900400506","article-title":"Analysis of Apparent Noncompetitive Responses to Competitive H1-Histamine Receptor Antagonists in Fluorescent Imaging Plate Reader-Based Calcium Assays","volume":"4","author":"Miller","year":"1999","journal-title":"J. Biomol. Screen"},{"issue":"23","key":"10.1016\/j.ejmech.2026.119082_bib94","doi-asserted-by":"crossref","first-page":"13674","DOI":"10.1073\/pnas.1835612100","article-title":"N-Desmethylclozapine, an Allosteric Agonist at Muscarinic 1 Receptor, Potentiates N-Methyl-d-aspartate Receptor Activity","volume":"100","author":"Sur","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119082_bib95","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/sj.bjp.0703931","article-title":"Dual Effects of Muscarinic M2 Acetylcholine Receptors on the Synthesis of Cyclic AMP in CHO cells: Dependence on Time, Receptor Density and Receptor Agonists","volume":"132","author":"Michal","year":"2001","journal-title":"Br. J. Pharmacol."},{"issue":"21","key":"10.1016\/j.ejmech.2026.119082_bib96","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1016\/S0024-3205(99)00488-9","article-title":"PD 102807, a Novel Muscarinic M4 Receptor Antagonist, Discriminates Between Striatal and Cortical Muscarinic Receptors Coupled to Cyclic AMP","volume":"65","author":"Olianas","year":"1999","journal-title":"Life Sci."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119082_bib97","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0031-6997(24)01362-0","article-title":"International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors","volume":"50","author":"Caulfield","year":"1998","journal-title":"Pharmacol. Rev."},{"key":"10.1016\/j.ejmech.2026.119082_bib98","doi-asserted-by":"crossref","first-page":"5627","DOI":"10.1038\/s41598-020-62344-w","article-title":"Cross-site and Cross-platform Variability of Automated Patch Clamp Assessments of Drug Effects on Human Cardiac Currents in Recombinant Cells","volume":"10","author":"Kramer","year":"2020","journal-title":"Sci. Rep."},{"issue":"11","key":"10.1016\/j.ejmech.2026.119082_bib99","doi-asserted-by":"crossref","first-page":"216","DOI":"10.21037\/atm.2016.05.18","article-title":"In Vitro Reactivity (\u201cOrgan Chamber\u201d) of Guinea Pig Tracheal Rings\u2014Methodology Considerations","volume":"4","author":"Albuquerque","year":"2016","journal-title":"Ann. Transl. Med."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119082_bib100","first-page":"506","article-title":"Euthanasia Method for Mice in Rapid Time-Course Pulmonary Pharmacokinetic Studies","volume":"48","author":"Schoell","year":"2009","journal-title":"J. Am. Assoc. Lab. Animal Sci."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426005271?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426005271?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:05:18Z","timestamp":1787040318000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523426005271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,11]]},"references-count":100,"alternative-id":["S0223523426005271"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119082","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2026,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Discovery and optimization of diarylsulfone-based dual M3-Antagonists and \u03b22-Agonists (MABAs) as inhaled bronchodilators","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119082","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"119082"}}