Novel 18beta-glycyrrhetinic acid analogues as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenases

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

doi:10.1016/j.bmc.2004.06.008

Novel 18beta-glycyrrhetinic acid analogues as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenases

Bioorg Med Chem. 2004 Aug 15;12(16):4439-57. doi: 10.1016/j.bmc.2004.06.008.

Authors

Xiangdong Su¹, Harshani Lawrence, Dharshini Ganeshapillai, Adrian Cruttenden, Atul Purohit, Michael J Reed, Nigel Vicker, Barry V L Potter

Affiliation

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

PMID: 15265495
DOI: 10.1016/j.bmc.2004.06.008

Abstract

Extensive structural modifications to the 18beta-glycyrrhetinic acid template are described and their effects on the SAR of the 11beta-hydroxysteroid dehydrogenase isozymes type 1 and 2 from the rat are investigated. Isoform selective inhibitors have been discovered and compound 7 N-(2-hydroxyethyl)-3beta-hydroxy-11-oxo-18beta-olean-12-en-30-oic acid amide is highlighted as a very potent selective inhibitor of 11beta-hydroxysteroid dehydrogenase 2 with an IC(50) = 4pM.

Publication types

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

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors*
Animals
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Glycyrrhetinic Acid / analogs & derivatives*
Glycyrrhetinic Acid / chemistry
Glycyrrhetinic Acid / pharmacology
Oleanolic Acid / analogs & derivatives*
Oleanolic Acid / chemistry
Oleanolic Acid / pharmacology
Rats

Substances

Enzyme Inhibitors
N-(2-hydroxyethyl)-3beta-hydroxy-11-oxo-18beta-olean-12-en-30-oic acid amide
Oleanolic Acid
11-beta-Hydroxysteroid Dehydrogenase Type 2
Glycyrrhetinic Acid