title: The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.
abstract: 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.
authors.affiliation: Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Chester
authors.initials: C
authors.lastname: Yuan
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.forename: Lynn
authors.initials: L
authors.lastname: Cai
authors.forename: Aiwen
authors.initials: A
authors.lastname: Li
authors.forename: Nianhe
authors.initials: N
authors.lastname: Han
authors.forename: George
authors.initials: G
authors.lastname: Moniz
authors.forename: Ben
authors.initials: B
authors.lastname: Askew
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
authors.forename: Lars
authors.initials: L
authors.lastname: Tedenborg
authors.forename: David
authors.initials: D
authors.lastname: Pyring
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Steven
authors.initials: S
authors.lastname: Jordan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Yaxiong
authors.initials: Y
authors.lastname: Sun
authors.forename: Maurice
authors.initials: M
authors.lastname: Emery
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
mesh_terms: 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*
chemical_list: D013844:Thiazoles; D005461:Fluorine; D002713:Chlorine; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1