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).
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.
Véniant
Murielle M
MM
Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
Hale
Clarence
C
Hungate
Randall W
RW
Gahm
Kyung
K
Emery
Maurice G
MG
Jona
Janan
J
Joseph
Smriti
S
Adams
Jeffrey
J
Hague
Andrew
A
Moniz
George
G
Zhang
Jiandong
J
Bartberger
Michael D
MD
Li
Vivian
V
Syed
Rashid
R
Jordan
Steven
S
Komorowski
Renée
R
Chen
Michelle M
MM
Cupples
Rod
R
Kim
Ki Won
KW
St Jean
David J
DJ
Johansson
Lars
L
Henriksson
Martin A
MA
Williams
Meredith
M
Vallgårda
Jerk
J
Fotsch
Christopher
C
Wang
Minghan
M
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*
C541878:AMG 221; D004791:Enzyme Inhibitors; D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1