2-(S)-phenethylaminothiazolones as potent, orally efficacious inhibitors of 11beta-hydroxysteriod dehydrogenase type 1.
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11beta-HSD1 could potentially treat metabolic syndrome as well as type 2 diabetes. Through modification of our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a Ki of 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11beta-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model.
Jean
David J St
DJ
Department of Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. david.st.jean@amgen.com
Yuan
Chester
C
Bercot
Eric A
EA
Cupples
Rod
R
Chen
Michelle
M
Fretland
Jenne
J
Hale
Clarence
C
Hungate
Randall W
RW
Komorowski
Renee
R
Veniant
Murielle
M
Wang
Minghan
M
Zhang
Xiping
X
Fotsch
Christopher
C
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D000273:Adipose Tissue / Q000201:enzymology; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human