A novel 18 beta-glycyrrhetinic acid analogue as a potent and selective inhibitor of 11 beta-hydroxysteroid dehydrogenase 2

Nigel Vicker; Xiangdong Su; Harshani Lawrence; Adrian Cruttenden; Atul Purohit; Michael J Reed; Barry V L Potter

doi:10.1016/j.bmcl.2004.03.107

A novel 18 beta-glycyrrhetinic acid analogue as a potent and selective inhibitor of 11 beta-hydroxysteroid dehydrogenase 2

Bioorg Med Chem Lett. 2004 Jun 21;14(12):3263-7. doi: 10.1016/j.bmcl.2004.03.107.

Authors

Nigel Vicker¹, Xiangdong Su, Harshani Lawrence, Adrian Cruttenden, Atul Purohit, Michael J Reed, Barry V L Potter

Affiliation

¹ Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Bath BA2 7AY, UK.

PMID: 15149687
DOI: 10.1016/j.bmcl.2004.03.107

Abstract

Using 18beta-glycyrrhetinic acid as a template, the synthesis of a series of secondary amides at the 30-position is described and the effects of these modifications on the SAR of the 11beta-hydroxysteroid dehydrogenase isozymes type 1 and 2 from the rat are investigated. An isoform selective inhibitor has been discovered and compound 5, N-(2-hydroxyethyl)-3beta-hydroxy-11-oxo-18beta-olean-12-en-30-oic acid amide, is highlighted as a very potent and selective inhibitor of 11beta-hydroxysteroid dehydrogenase 2 with an IC(50)=4 pM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
Animals
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Glucuronides / chemistry*
Glucuronides / pharmacology
Glycyrrhetinic Acid / analogs & derivatives*
Glycyrrhetinic Acid / chemistry*
Glycyrrhetinic Acid / pharmacology
Rats
Rats, Wistar

Substances

18beta-glycyrrhetinic acid-3-O-beta-D-glucuronide
Enzyme Inhibitors
Glucuronides
11-beta-Hydroxysteroid Dehydrogenase Type 2
Glycyrrhetinic Acid