The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.
A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.
Yuan
Chester
C
Amgen Inc., Thousand Oaks, CA 91320, USA.
St Jean
David J
DJ
Liu
Qingyian
Q
Cai
Lynn
L
Li
Aiwen
A
Han
Nianhe
N
Moniz
George
G
Askew
Ben
B
Hungate
Randall W
RW
Johansson
Lars
L
Tedenborg
Lars
L
Pyring
David
D
Williams
Meredith
M
Hale
Clarence
C
Chen
Michelle
M
Cupples
Rod
R
Zhang
Jiandong
J
Jordan
Steven
S
Bartberger
Michael D
MD
Sun
Yaxiong
Y
Emery
Maurice
M
Wang
Minghan
M
Fotsch
Christopher
C
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D002713:Chlorine / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*
D013844:Thiazoles; D005461:Fluorine; D002713:Chlorine; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1