Design, synthesis, and SAR studies of novel polycyclic acids as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

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

doi:10.1016/j.bmcl.2011.09.055

Design, synthesis, and SAR studies of novel polycyclic acids as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6699-704. doi: 10.1016/j.bmcl.2011.09.055. Epub 2011 Sep 21.

Authors

Xiang-Yang Ye¹, Stephanie Y Chen, Akbar Nayeem, Rajasree Golla, Ramakrishna Seethala, Mengmeng Wang, Timothy Harper, Bogdan G Sleczka, Yi-Xin Li, Bin He, Mark Kirby, David A Gordon, Jeffrey A Robl

Affiliation

¹ Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA. [email protected]

PMID: 21983439
DOI: 10.1016/j.bmcl.2011.09.055

Abstract

Starting from high throughput screening hit 2-adamantyl acetic acid 3, a series of polycyclic acids have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD-1. Structure-activity relationships of two different regions of the chemotype (polycyclic ring and substituents on quaternary carbon) are discussed.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Acetic Acid / chemistry
Acetic Acid / pharmacology
Acids / chemistry
Acids / pharmacology*
Adamantane / analogs & derivatives
Adamantane / pharmacology*
Diabetes Mellitus, Type 2 / drug therapy
Drug Design*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Protein Binding
Structure-Activity Relationship

Substances

Acids
Enzyme Inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1
HSD11B1 protein, human
Adamantane
Acetic Acid