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With human liver microsomes, daridorexant underwent hydroxylation at the methyl group of the benzimidazole moiety, oxidative O\u2010demethylation of the anisole to the corresponding phenol, and hydroxylation to a 4\u2010hydroxy piperidinol derivative. While the chemical structures of the benzylic alcohol and the phenol proved to be products of standard P450 reactions, 1D and 2D\u2005NMR data of the latter hydroxylation product was incompatible with the initially postulated hydroxylation of the pyrrolidine ring and suggested the disappearance of the pyrrolidine ring and formation of a new 6\u2010membered ring. Its formation is best explained by initial hydroxylation of the pyrrolidine ring in 5\u2010position to yield a cyclic hemiaminal. Hydrolytic ring opening then results in an aldehyde that subsequently cyclizes onto one of the benzimidazole nitrogen atoms to yield the final 4\u2010hydroxy piperidinol. The proposed mechanism was substantiated using an N\u2010methylated analogue, which might hydrolyze to the open\u2010chain aldehyde but cannot undergo the final cyclization step. CYP3A4 was the major P450 enzyme responsible for daridorexant metabolism, accounting for 89\u2009% of metabolic turnover.<\/jats:p>","DOI":"10.1002\/cmdc.202300030","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T07:52:05Z","timestamp":1678348325000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["CYP3A4 Catalyzes the Rearrangement of the Dual Orexin Receptor Antagonist Daridorexant to 4\u2010Hydroxypiperidinol Metabolites"],"prefix":"10.1002","volume":"18","author":[{"given":"Alexander","family":"Treiber","sequence":"first","affiliation":[{"name":"Non-Clinical Drug Metabolism and Pharmacokinetics Idorsia Pharmaceuticals Ltd.  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