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Synthesis, in Vitro Covalent Binding Evaluation, and Metabolism of (14)C-Labeled Inhibitors of 11?-HSD1.

ABSTRACT: In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11?-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.

SUBMITTER: Sun D

PROVIDER: S-EPMC4233368 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Synthesis, in Vitro Covalent Binding Evaluation, and Metabolism of (14)C-Labeled Inhibitors of 11β-HSD1.

Sun Daqing D Ye Qiuping Q Yan Xuelei X Rew Yosup Y Fan Peter P He Xiao X Jiang Min M McMinn Dustin L DL Monshouwer Mario M Tu Hua H Powers Jay P JP

ACS medicinal chemistry letters 20140923 11

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 h ...[more]

PMID: 25408839

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