Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.
High-throughput screening identified 5 as a weak inhibitor of 11beta-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to >700-fold over 11beta-HSD2. Analogues which showed >50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.
Coppola
Gary M
GM
Department of Metabolic and Cardiovascular Diseases, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. gary.coppola@novartis.com
Kukkola
Paivi J
PJ
Stanton
James L
JL
Neubert
Alan D
AD
Marcopulos
Nicholas
N
Bilci
Natalie A
NA
Wang
Hua
H
Tomaselli
Hollis C
HC
Tan
Jenny
J
Aicher
Thomas D
TD
Knorr
Douglas C
DC
Jeng
Arco Y
AY
Dardik
Beatriz
B
Chatelain
Ricardo E
RE
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000315:Adrenalectomy; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D006873:Hydroquinones; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone