title: 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.
abstract: 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.
authors.affiliation: Department of Chemical Research and Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. cfotsch@amgen.com
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Eric A
authors.initials: EA
authors.lastname: Bercot
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.forename: Maury
authors.initials: M
authors.lastname: Emery
authors.forename: Jenne
authors.initials: J
authors.lastname: Fretland
authors.forename: Anil
authors.initials: A
authors.lastname: Guram
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: Nianhe
authors.initials: N
authors.lastname: Han
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Michael
authors.initials: M
authors.lastname: Hayashi
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.forename: Guy
authors.initials: G
authors.lastname: Matsumoto
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
authors.forename: Stefania
authors.initials: S
authors.lastname: Ursu
authors.forename: Murielle
authors.initials: M
authors.lastname: Véniant
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.forename: Chester
authors.initials: C
authors.lastname: Yuan
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Tu
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
mesh_terms: 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
chemical_list: 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