{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:09:38Z","timestamp":1785434978800,"version":"3.56.0"},"reference-count":39,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic &amp; Medicinal Chemistry Letters"],"published-print":{"date-parts":[[2024,3]]},"DOI":"10.1016\/j.bmcl.2024.129629","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T01:10:12Z","timestamp":1706577012000},"page":"129629","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":12,"special_numbering":"C","title":["Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist"],"prefix":"10.1016","volume":"100","author":[{"given":"Angela","family":"Glen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland W.","family":"B\u00fcrli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Livermore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3754-4015","authenticated-orcid":false,"given":"William","family":"Buffham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7232-2407","authenticated-orcid":false,"given":"Stephanie","family":"Merison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5607-2470","authenticated-orcid":false,"given":"Anna E.","family":"Rowland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Fieldhouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9656-3024","authenticated-orcid":false,"given":"David J.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee A.","family":"Dawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark B.","family":"Carlton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4533-9369","authenticated-orcid":false,"given":"Nicola L.","family":"Brice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmcl.2024.129629_b0005","doi-asserted-by":"crossref","first-page":"691","DOI":"10.3389\/fnins.2020.00691","article-title":"Evolution of orexin neuropeptide system: structure and function","volume":"14","author":"Soya","year":"2020","journal-title":"Front Neurosci"},{"key":"10.1016\/j.bmcl.2024.129629_b0010","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/bph.12261","article-title":"Discovery and development of orexin receptor antagonists as therapeutics for insomnia","volume":"171","author":"Winrow","year":"2014","journal-title":"Br J Pharmacol"},{"key":"10.1016\/j.bmcl.2024.129629_b0015","doi-asserted-by":"crossref","DOI":"10.1016\/j.peptides.2023.171051","article-title":"The present and future of synthetic orexin receptor agonists","volume":"167","author":"Saitoh","year":"2023","journal-title":"Peptides"},{"key":"10.1016\/j.bmcl.2024.129629_b0020","doi-asserted-by":"crossref","unstructured":"Muehlan C, Roch C, Vaillant C, Dingemanse J. The orexin story and orexin receptor antagonists for the treatment of insomnia. J. Sleep. Res. Published online April 2023:e13902. doi:10.1111\/jsr.13902.","DOI":"10.1111\/jsr.13902"},{"key":"10.1016\/j.bmcl.2024.129629_b0025","doi-asserted-by":"crossref","DOI":"10.1016\/j.yfrne.2023.101066","article-title":"Targeting the orexin\/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies","volume":"69","author":"Ten-Blanco","year":"2023","journal-title":"Front Neuroendocrinol"},{"key":"10.1016\/j.bmcl.2024.129629_b0030","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1038\/s42255-022-00677-8","article-title":"Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction","volume":"4","author":"Schneeberger","year":"2022","journal-title":"Nat Metab"},{"key":"10.1016\/j.bmcl.2024.129629_b0035","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nm.2075","article-title":"A key role for orexin in panic anxiety","volume":"16","author":"Johnson","year":"2010","journal-title":"Nat Med"},{"key":"10.1016\/j.bmcl.2024.129629_b0040","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1038\/npp.2012.48","article-title":"Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats","volume":"37","author":"Piccoli","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"10.1016\/j.bmcl.2024.129629_b0045","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1021\/acs.jmedchem.9b01787","article-title":"Comparison of orexin 1 and orexin 2 ligand binding modes using x-ray crystallography and computational analysis","volume":"63","author":"Rappas","year":"2020","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2024.129629_b0050","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1093\/ijnp\/pyab050","article-title":"Efficacy and safety of seltorexant as adjunctive therapy in major depressive disorder: a phase 2b, randomized, placebo-controlled, adaptive dose-finding study","volume":"24","author":"Savitz","year":"2021","journal-title":"Int J Neuropsychopharmacol"},{"key":"10.1016\/j.bmcl.2024.129629_b0055","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0014-5793(98)01266-6","article-title":"Distribution of orexin receptor mRNA in the rat brain","volume":"438","author":"Trivedi","year":"1998","journal-title":"FEBS Lett"},{"key":"10.1016\/j.bmcl.2024.129629_b0060","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/cne.1190","article-title":"Differential expression of orexin receptors 1 and 2 in the rat brain","volume":"435","author":"Marcus","year":"2001","journal-title":"J Comp Neurol"},{"key":"10.1016\/j.bmcl.2024.129629_b0065","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.brainres.2016.01.049","article-title":"The highly selective orexin\/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice","volume":"1636","author":"Lopez","year":"2016","journal-title":"Brain Res"},{"key":"10.1016\/j.bmcl.2024.129629_b0070","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1111\/j.1460-9568.2009.07065.x","article-title":"The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system","volume":"31","author":"Espa\u00f1a","year":"2010","journal-title":"Eur J Neurosci"},{"key":"10.1016\/j.bmcl.2024.129629_b0075","article-title":"Understanding the role of orexin neuropeptides in drug addiction: preclinical studies and translational value","volume":"15","author":"Matzeu","year":"2021","journal-title":"Front Behav Neurosci"},{"key":"10.1016\/j.bmcl.2024.129629_b0080","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1124\/jpet.114.220392","article-title":"A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects","volume":"352","author":"Bonaventure","year":"2015","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1016\/j.bmcl.2024.129629_b0085","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuint.2009.08.012","article-title":"The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization","volume":"56","author":"Quarta","year":"2010","journal-title":"Neurochem Int"},{"key":"10.1016\/j.bmcl.2024.129629_b0090","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3389\/fnins.2014.00107","article-title":"Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex","volume":"8","author":"Aluisio","year":"2014","journal-title":"Front Neurosci"},{"key":"10.1016\/j.bmcl.2024.129629_b0095","doi-asserted-by":"crossref","first-page":"7421","DOI":"10.1523\/JNEUROSCI.1587-04.2004","article-title":"Orexin-A infusion in the locus ceruleus triggers norepinephrine (NE) release and NE-induced long-term potentiation in the dentate gyrus","volume":"24","author":"Walling","year":"2004","journal-title":"J Neurosci"},{"key":"10.1016\/j.bmcl.2024.129629_b0100","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.brainres.2008.10.041","article-title":"Interaction between orexinergic neurons and NMDA receptors in the control of locus coeruleus-cerebrocortical noradrenergic activity of the rat","volume":"1250","author":"Tose","year":"2009","journal-title":"Brain Res"},{"key":"10.1016\/j.bmcl.2024.129629_b0105","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1093\/ijnp\/pyy075","article-title":"Orexin-a levels in relation to the risk of metabolic syndrome in patients with schizophrenia taking antipsychotics","volume":"22","author":"Chen","year":"2019","journal-title":"Int J Neuropsychopharmacol"},{"key":"10.1016\/j.bmcl.2024.129629_b0110","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.psyneuen.2014.12.012","article-title":"Elevated plasma orexin A levels in a subgroup of patients with schizophrenia associated with fewer negative and disorganized symptoms","volume":"53","author":"Chien","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"10.1016\/j.bmcl.2024.129629_b0115","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1080\/08039488.2020.1755995","article-title":"A higher body mass index in Chinese in patients with chronic schizophrenia is associated with elevated plasma orexin-A levels and fewer negative symptoms","volume":"74","author":"Liu","year":"2020","journal-title":"Nord J Psychiatry"},{"key":"10.1016\/j.bmcl.2024.129629_b0120","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1111\/bcp.14251","article-title":"First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist","volume":"86","author":"Kaufmann","year":"2020","journal-title":"Br J Clin Pharmacol"},{"key":"10.1016\/j.bmcl.2024.129629_b0125","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/s41398-020-00937-9","article-title":"Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans","volume":"10","author":"Salvadore","year":"2020","journal-title":"Transl Psychiatry"},{"key":"10.1016\/j.bmcl.2024.129629_b0130","doi-asserted-by":"crossref","first-page":"14937","DOI":"10.1074\/jbc.M111.334300","article-title":"Intramolecular fluorescence resonance energy transfer (FRET) sensors of the orexin OX1 and OX2 receptors identify slow kinetics of agonist activation","volume":"287","author":"Xu","year":"2012","journal-title":"J Biol Chem"},{"key":"10.1016\/j.bmcl.2024.129629_b0135","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1146\/annurev-pharmtox-010716-104837","article-title":"The discovery of suvorexant, the first orexin receptor drug for insomnia","volume":"57","author":"Coleman","year":"2017","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"10.1016\/j.bmcl.2024.129629_b0140","doi-asserted-by":"crossref","first-page":"7559","DOI":"10.1021\/jm060642i","article-title":"Structure\u2212brain exposure relationships","volume":"49","author":"Hitchcock","year":"2006","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2024.129629_b0145","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1021\/jm100087s","article-title":"Intramolecular hydrogen bonding in medicinal chemistry","volume":"53","author":"Kuhn","year":"2010","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2024.129629_b0150","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10822-014-9710-x","article-title":"Shaping suvorexant: Application of experimental and theoretical methods for driving synthetic designs","volume":"28","author":"McGaughey","year":"2014","journal-title":"J Comput Aided Mol Des"},{"key":"10.1016\/j.bmcl.2024.129629_b0155","doi-asserted-by":"crossref","first-page":"12059","DOI":"10.1002\/anie.201405364","article-title":"Improving on nature: making a cyclic heptapeptide orally bioavailable","volume":"53","author":"Nielsen","year":"2014","journal-title":"Angew. Chemie Int. Ed."},{"key":"10.1016\/j.bmcl.2024.129629_b0160","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nsmb.3183","article-title":"Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors","volume":"23","author":"Yin","year":"2016","journal-title":"Nat Struct Mol Biol"},{"key":"10.1016\/j.bmcl.2024.129629_b0165","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/bph.12245","article-title":"Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands","volume":"171","author":"Mould","year":"2014","journal-title":"Br J Pharmacol"},{"key":"10.1016\/j.bmcl.2024.129629_b0170","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3389\/fnins.2013.00230","article-title":"Kinetic properties of \u201cdual\u201d orexin receptor antagonists at OX1R and OX2R orexin receptors","volume":"7","author":"Callander","year":"2013","journal-title":"Front Neurosci"},{"key":"10.1016\/j.bmcl.2024.129629_b0175","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1021\/acs.oprd.8b00349","article-title":"Highly Selective Synthesis of 2-(2H\u20131,2,3-Triazol-2-yl)benzoic Acids","volume":"23","author":"Roth","year":"2019","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.bmcl.2024.129629_b0180","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1124\/jpet.109.152009","article-title":"Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat","volume":"330","author":"Dugovic","year":"2009","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1016\/j.bmcl.2024.129629_b0185","unstructured":"Fieldhouse C., Glen A., Maine S., Fujimoto T., Robinson J.S. 1,2-substituted cyclopentanes as orexin receptor antagonists. https:\/\/pubchem.ncbi.nlm.nih.gov\/patent\/US-10011588-B2."},{"key":"10.1016\/j.bmcl.2024.129629_b0190","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1124\/jpet.117.241422","article-title":"In vitro and in silico characterization of lemborexant (E2006), a novel dual orexin receptor antagonist","volume":"362","author":"Beuckmann","year":"2017","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1016\/j.bmcl.2024.129629_b0195","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1124\/jpet.115.225466","article-title":"Characterization of JNJ-42847922, a selective orexin-2 receptor antagonist, as a clinical candidate for the treatment of insomnia","volume":"354","author":"Bonaventure","year":"2015","journal-title":"J Pharmacol Exp Ther"}],"container-title":["Bioorganic &amp; Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X24000313?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X24000313?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T07:49:22Z","timestamp":1760773762000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0960894X24000313"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3]]},"references-count":39,"alternative-id":["S0960894X24000313"],"URL":"https:\/\/doi.org\/10.1016\/j.bmcl.2024.129629","relation":{},"ISSN":["0960-894X"],"issn-type":[{"value":"0960-894X","type":"print"}],"subject":[],"published":{"date-parts":[[2024,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmcl.2024.129629","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 The Author(s). Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}],"article-number":"129629"}}