Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Xiang-Yang Ye; David Yoon; Stephanie Y Chen; Akbar Nayeem; Rajasree Golla; Ramakrishna Seethala; Mengmeng Wang; Timothy Harper; Bogdan G Sleczka; Atsu Apedo; Yi-Xin Li; Bin He; Mark Kirby; David A Gordon; Jeffrey A Robl

doi:10.1016/j.bmcl.2013.11.066

Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Bioorg Med Chem Lett. 2014 Jan 15;24(2):654-60. doi: 10.1016/j.bmcl.2013.11.066. Epub 2013 Dec 5.

Authors

Xiang-Yang Ye¹, David Yoon², Stephanie Y Chen², Akbar Nayeem³, Rajasree Golla⁴, Ramakrishna Seethala⁴, Mengmeng Wang⁵, Timothy Harper⁵, Bogdan G Sleczka⁶, Atsu Apedo⁶, Yi-Xin Li⁶, Bin He⁷, Mark Kirby⁷, David A Gordon⁷, Jeffrey A Robl⁸

Affiliations

¹ Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States. Electronic address: [email protected].
² Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
³ CADD, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
⁴ Lead Evaluation, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
⁵ MAP, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
⁶ BDAS, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
⁷ Department of Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
⁸ Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States. Electronic address: [email protected].

PMID: 24360604
DOI: 10.1016/j.bmcl.2013.11.066

Abstract

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11β-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11β-HSD1 with a favorable development profile.

Keywords: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1); Enzyme inhibitor; Structure–activity relationships (SAR).

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Adamantane / chemical synthesis*
Adamantane / pharmacology
Animals
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Humans
Mice
Mice, Transgenic
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Protein Structure, Secondary
Structure-Activity Relationship
Tetrazoles / chemical synthesis*
Tetrazoles / pharmacology

Substances

Enzyme Inhibitors
Tetrazoles
11-beta-Hydroxysteroid Dehydrogenase Type 1
HSD11B1 protein, human
Adamantane