Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017).
Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.
Cardiovascular and Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. jamie.scott@astrazeneca.com
James S
JS
Scott
Suzanne S
SS
Bowker
Joanne
J
Deschoolmeester
Stefan
S
Gerhardt
David
D
Hargreaves
Elaine
E
Kilgour
Adele
A
Lloyd
Rachel M
RM
Mayers
William
W
McCoull
Nicholas J
NJ
Newcombe
Derek
D
Ogg
Martin J
MJ
Packer
Amanda
A
Rees
John
J
Revill
Paul
P
Schofield
Nidhal
N
Selmi
John G
JG
Swales
Paul R O
PR
Whittamore
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D013379:Substrate Specificity
C574773:2-(1-(5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl)-3-piperidyl)acetic acid; D004791:Enzyme Inhibitors; D010880:Piperidines; D009536:Niacinamide; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1