title: Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes.
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.
authors.affiliation: 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.
authors.forename: Aiwen
authors.initials: A
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Chester C
authors.initials: CC
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Chow
authors.affiliation: 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.
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Maurice G
authors.initials: MG
authors.lastname: Emery
authors.affiliation: 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.
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.affiliation: 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.
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
authors.affiliation: 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.
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.affiliation: 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.
authors.forename: Murielle
authors.initials: M
authors.lastname: Véniant
authors.affiliation: 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.
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
keywords: 11β-HSD1 inhibitors; AMG 221; clinical candidate; metabolites