Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes
ACS Medicinal Chemistry Letters2011Vol. 2(11), pp. 824–827
Citations Over TimeTop 22% of 2011 papers
Aiwen Li, Chester Yuan, David Chow, Michelle Chen, Maurice G. Emery, Clarence Hale, Xiping Zhang, Raju Subramanian, David J. St. Jean, Renée Komorowski, Murielle M. Véniant, Minghan Wang, Christopher Fotsch
Abstract
All eight of the major active metabolites of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed by comparison with samples generated in liver microsomes. After further profiling, we determined that metabolite 2 was equipotent to 1 on human 11β-HSD1 and had lower in vivo clearance and higher bioavailability in rat and mouse. Compound 2 was advanced into a pharmacodynamic model in mouse where it inhibited adipose 11β-HSD1 activity.
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