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.
Aiwen Li  1 ,  Chester C Yuan  1 ,  David Chow  1 ,  Michelle Chen  1 ,  Maurice G Emery  1 ,  Clarence Hale  1 ,  Xiping Zhang  1 ,  Raju Subramanian  1 ,  David J St Jean Jr  1 ,  Renee Komorowski  1 ,  Murielle Véniant  1 ,  Minghan Wang  1 ,  Christopher Fotsch  1
Affiliations
  • 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.
PMID: 24900270 DOI: 10.1021/ml2001467
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.
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