{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T07:39:58Z","timestamp":1778830798799,"version":"3.51.4"},"reference-count":23,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"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":["Bioorganic & Medicinal Chemistry Letters"],"published-print":{"date-parts":[[2023,10]]},"DOI":"10.1016\/j.bmcl.2023.129454","type":"journal-article","created":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T11:44:17Z","timestamp":1692099857000},"page":"129454","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":8,"special_numbering":"C","title":["6-Azaspiro[2.5]octanes as small molecule agonists of the human glucagon-like peptide-1 receptor"],"prefix":"10.1016","volume":"94","author":[{"given":"Gary E.","family":"Aspnes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7365-7332","authenticated-orcid":false,"given":"Scott W.","family":"Bagley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven B.","family":"Coffey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward L.","family":"Conn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9033-5952","authenticated-orcid":false,"given":"John M.","family":"Curto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9234-8618","authenticated-orcid":false,"given":"David J.","family":"Edmonds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julien","family":"Genovino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7592-2478","authenticated-orcid":false,"given":"David A.","family":"Griffith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gajendra","family":"Ingle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhua","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2987-680X","authenticated-orcid":false,"given":"Chris","family":"Limberakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan M.","family":"Mathiowetz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4659-6300","authenticated-orcid":false,"given":"David W.","family":"Piotrowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin R.","family":"Rose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9813-1882","authenticated-orcid":false,"given":"Roger B.","family":"Ruggeri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1992-7714","authenticated-orcid":false,"given":"Liuqing","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmcl.2023.129454_b0005","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/j.tibs.2017.10.003","article-title":"Extending the Structural View of Class B GPCRs","volume":"42","author":"de Graaf","year":"2017","journal-title":"Trends Biochem Sci"},{"key":"10.1016\/j.bmcl.2023.129454_b0010","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1016\/S0140-6736(87)91194-9","article-title":"Glucagon-like peptide-1 7\u201336: A physiological incretin in man","volume":"330","author":"Kreymann","year":"1987","journal-title":"Lancet"},{"key":"10.1016\/j.bmcl.2023.129454_b0015","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1210\/endo-119-4-1467","article-title":"Glucagon-Like Peptides GLP-1 and GLP-2, Predicted Products of the Glucagon Gene, Are Secreted Separately from Pig Small Intestine but Not Pancreas*","volume":"119","author":"\u00d8rskov","year":"1986","journal-title":"Endocrinology"},{"key":"10.1016\/j.bmcl.2023.129454_b0020","doi-asserted-by":"crossref","first-page":"E981","DOI":"10.1152\/ajpendo.1997.273.5.E981","article-title":"Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans","volume":"273","author":"Nauck","year":"1997","journal-title":"Am J Phys Endocrinol"},{"key":"10.1016\/j.bmcl.2023.129454_b0025","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cmet.2018.03.001","article-title":"Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1","volume":"27","author":"Drucker","year":"2018","journal-title":"Cell Metab"},{"key":"10.1016\/j.bmcl.2023.129454_b0030","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/obr.12465","article-title":"Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity","volume":"18","author":"Burcelin","year":"2017","journal-title":"Obes Rev"},{"key":"10.1016\/j.bmcl.2023.129454_b0035","unstructured":"Novo Nordisk A\/S, WEGOVY (semaglutide) prescribing information. 2021."},{"key":"10.1016\/j.bmcl.2023.129454_b0040","unstructured":"Novo Nordisk A\/S. RYBELSUS\u00ae (semaglutide) prescribing information 2020. https:\/\/www.novo-pi.com\/rybelsus.pdf (accessed August 12, 2020)."},{"key":"10.1016\/j.bmcl.2023.129454_b0045","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/s41591-021-01391-w","article-title":"Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial","volume":"27","author":"Saxena","year":"2021","journal-title":"Nat Med"},{"key":"10.1016\/j.bmcl.2023.129454_b0050","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1358\/dof.2022.47.6.3373535","article-title":"Glucagon-like peptide 1 receptor agonist, Treatment of type 2 diabetes, Treatment of obesity","volume":"47","author":"Sperry","year":"2022","journal-title":"Drugs Future"},{"key":"10.1016\/j.bmcl.2023.129454_b0055","doi-asserted-by":"crossref","unstructured":"Kawai, T.; Tanino, F.; Fukazawa, M.; Ogawa, K.; Nagao, S.; Yoshino, H.; Komatsu, S.-I.; Suzuki, Y.; Kawabe, Y., OWL833, an Orally Active Nonpeptide GLP-1 Receptor Agonist, Improves Glucose Tolerance by Increasing Insulin Secretion and Reduces Food Intake of Cynomolgus Monkeys. Diabetes 2018, 67 (Supplement_1).","DOI":"10.2337\/db18-1118-P"},{"key":"10.1016\/j.bmcl.2023.129454_b0060","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/s41586-019-1902-z","article-title":"Activation of the GLP-1 receptor by a non-peptidic agonist","volume":"577","author":"Zhao","year":"2020","journal-title":"Nature"},{"key":"10.1016\/j.bmcl.2023.129454_b0065","doi-asserted-by":"crossref","first-page":"8208","DOI":"10.1021\/acs.jmedchem.1c01856","article-title":"A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor","volume":"65","author":"Griffith","year":"2022","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2023.129454_b0070","article-title":"The Boron-Wittig Olefination of Aldehydes and Ketones with Bis[(pinacolato)boryl]methane: an Extended Reaction Scope","volume":"5624\u20135635","author":"Kovalenko","year":"2019","journal-title":"Eur J Org Chem"},{"key":"10.1016\/j.bmcl.2023.129454_b0075","doi-asserted-by":"crossref","first-page":"6401","DOI":"10.1021\/acs.jmedchem.8b00077","article-title":"Lipophilic Efficiency as an Important Metric in Drug Design","volume":"61","author":"Johnson","year":"2018","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2023.129454_b0080","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nature25773","article-title":"Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor\u2013Gs complex","volume":"555","author":"Liang","year":"2018","journal-title":"Nature"},{"key":"10.1016\/j.bmcl.2023.129454_b0085","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nature22394","article-title":"Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein","volume":"546","author":"Zhang","year":"2017","journal-title":"Nature"},{"key":"10.1016\/j.bmcl.2023.129454_b0090","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.molcel.2020.09.020","article-title":"Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists","volume":"80","author":"Zhang","year":"2020","journal-title":"Mol Cell"},{"key":"10.1016\/j.bmcl.2023.129454_b0095","doi-asserted-by":"crossref","first-page":"13815","DOI":"10.1021\/jacs.2c04986","article-title":"The Role of Tryptophan in \u03c0 Interactions in Proteins: An Experimental Approach","volume":"144","author":"Shao","year":"2022","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2023.129454_b0100","doi-asserted-by":"crossref","first-page":"4974","DOI":"10.1002\/jps.22674","article-title":"Development of a new permeability assay using low-efflux MDCKII cells","volume":"100","author":"Di","year":"2011","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.bmcl.2023.129454_b0105","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S2213-8587(17)30413-8","article-title":"GLP-1 receptor agonists: differentiation within the class","volume":"6","author":"Taylor","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"10.1016\/j.bmcl.2023.129454_b0110","doi-asserted-by":"crossref","first-page":"3785","DOI":"10.1007\/s11095-015-1749-4","article-title":"Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS)","volume":"32","author":"Varma","year":"2015","journal-title":"Pharm Res"},{"key":"10.1016\/j.bmcl.2023.129454_b0115","doi-asserted-by":"crossref","first-page":"038","DOI":"10.4172\/2161-0444.1000495","article-title":"1-Aminobenzotriazole: A Mechanism-Based Cytochrome P450 Inhibitor and Probe of Cytochrome P450 Biology","volume":"8","author":"de Montellano","year":"2018","journal-title":"Med Chem"}],"container-title":["Bioorganic & Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X23003323?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X23003323?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T07:48:19Z","timestamp":1760773699000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0960894X23003323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10]]},"references-count":23,"alternative-id":["S0960894X23003323"],"URL":"https:\/\/doi.org\/10.1016\/j.bmcl.2023.129454","relation":{},"ISSN":["0960-894X"],"issn-type":[{"value":"0960-894X","type":"print"}],"subject":[],"published":{"date-parts":[[2023,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"6-Azaspiro[2.5]octanes as small molecule agonists of the human glucagon-like peptide-1 receptor","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmcl.2023.129454","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"129454"}}