Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes

Aiwen Li; Chester C Yuan; David Chow; Michelle Chen; Maurice G Emery; Clarence Hale; Xiping Zhang; Raju Subramanian; David J St Jean Jr; Renee Komorowski; Murielle Véniant; Minghan Wang; Christopher Fotsch

doi:10.1021/ml2001467

Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes

ACS Med Chem Lett. 2011 Sep 13;2(11):824-7. doi: 10.1021/ml2001467. eCollection 2011 Nov 10.

Affiliation

¹ Departments of Chemistry Research and Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.

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.

Keywords: 11β-HSD1 inhibitors; AMG 221; clinical candidate; metabolites.