title: Synthesis, in Vitro Covalent Binding Evaluation, and Metabolism of (14)C-Labeled Inhibitors of 11β-HSD1.
abstract: In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11β-HSD1 inhibitors labeled with (14)C: AMG 456 (1), AM-6949 (2), and AM-7715 (3). We evaluated the covalent protein binding of the labeled inhibitors in human liver microsomes in vitro and assessed their potential bioactivation risk in humans. We then studied the in vitro mechanism of 2 in human hepatocytes and the formation of reactive intermediates. Our study results suggest that 1 and 3 have low potential for metabolic bioactivation in humans, while 2 has relatively high risk.
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xuelei
authors.initials: X
authors.lastname: Yan
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Fan
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Dustin L
authors.initials: DL
authors.lastname: McMinn
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Mario
authors.initials: M
authors.lastname: Monshouwer
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Hua
authors.initials: H
authors.lastname: Tu
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
keywords: 11β-HSD1; 11β-HSD2; 4,4-disubstituted cyclohexylbenzamides; arylsulfonylpiperazine; bioactiviation; covalent protein binding; diabetes; diarylsulfone; hydroxysteroid dehydrogenase; metabolic syndrome; radiolabeled inhibitor; reactive metabolite