Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: reducing pregnane X receptor activity and exploring activity in a monkey pharmacodynamic model.
A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.
Fotsch
Christopher
C
Department of Chemical Research and Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. cfotsch@amgen.com
Bartberger
Michael D
MD
Bercot
Eric A
EA
Chen
Michelle
M
Cupples
Rod
R
Emery
Maury
M
Fretland
Jenne
J
Guram
Anil
A
Hale
Clarence
C
Han
Nianhe
N
Hickman
Dean
D
Hungate
Randall W
RW
Hayashi
Michael
M
Komorowski
Renee
R
Liu
Qingyian
Q
Matsumoto
Guy
G
St Jean
David J
DJ
Ursu
Stefania
S
Véniant
Murielle
M
Xu
Guifen
G
Ye
Qiuping
Q
Yuan
Chester
C
Zhang
Jiandong
J
Zhang
Xiping
X
Tu
Hua
H
Wang
Minghan
M
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism*; D014018:Tissue Distribution
D004791:Enzyme Inhibitors; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human