A novel 18 beta-glycyrrhetinic acid analogue as a potent and selective inhibitor of 11 beta-hydroxysteroid dehydrogenase 2.
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.
Vicker
Nigel
N
Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Bath BA2 7AY, UK.
Su
Xiangdong
X
Lawrence
Harshani
H
Cruttenden
Adrian
A
Purohit
Atul
A
Reed
Michael J
MJ
Potter
Barry V L
BV
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020719:Glucuronides / Q000737:chemistry* / Q000494:pharmacology; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
C492689:18beta-glycyrrhetinic acid-3-O-beta-D-glucuronide; D004791:Enzyme Inhibitors; D020719:Glucuronides; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006034:Glycyrrhetinic Acid