title: 2-(S)-phenethylaminothiazolones as potent, orally efficacious inhibitors of 11beta-hydroxysteriod dehydrogenase type 1.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. david.st.jean@amgen.com
authors.forename: David J St
authors.initials: DJ
authors.lastname: Jean
authors.forename: Chester
authors.initials: C
authors.lastname: Yuan
authors.forename: Eric A
authors.initials: EA
authors.lastname: Bercot
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.forename: Jenne
authors.initials: J
authors.lastname: Fretland
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.forename: Murielle
authors.initials: M
authors.lastname: Veniant
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
mesh_terms: 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
chemical_list: D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human