title: Discovery of a potent, orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for clinical study: identification of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221).
abstract: Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Kyung
authors.initials: K
authors.lastname: Gahm
authors.forename: Maurice G
authors.initials: MG
authors.lastname: Emery
authors.forename: Janan
authors.initials: J
authors.lastname: Jona
authors.forename: Smriti
authors.initials: S
authors.lastname: Joseph
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Adams
authors.forename: Andrew
authors.initials: A
authors.lastname: Hague
authors.forename: George
authors.initials: G
authors.lastname: Moniz
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Vivian
authors.initials: V
authors.lastname: Li
authors.forename: Rashid
authors.initials: R
authors.lastname: Syed
authors.forename: Steven
authors.initials: S
authors.lastname: Jordan
authors.forename: Renée
authors.initials: R
authors.lastname: Komorowski
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Chen
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Kim
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
authors.forename: Martin A
authors.initials: MA
authors.lastname: Henriksson
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Jerk
authors.initials: J
authors.lastname: Vallgårda
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D013844:Thiazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C541878:AMG 221; D004791:Enzyme Inhibitors; D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1