Abstract
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.
MeSH terms
-
11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
-
11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
-
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
-
Administration, Oral
-
Animals
-
Biological Availability
-
Dogs
-
Drug Discovery*
-
Enzyme Inhibitors / administration & dosage
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacokinetics*
-
Enzyme Inhibitors / pharmacology*
-
Humans
-
Inhibitory Concentration 50
-
Male
-
Mice
-
Models, Molecular
-
Niacinamide / administration & dosage
-
Niacinamide / analogs & derivatives*
-
Niacinamide / metabolism
-
Niacinamide / pharmacokinetics
-
Niacinamide / pharmacology
-
Piperidines / administration & dosage
-
Piperidines / metabolism
-
Piperidines / pharmacokinetics*
-
Piperidines / pharmacology*
-
Protein Conformation
-
Rats
-
Substrate Specificity
Substances
-
2-(1-(5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl)-3-piperidyl)acetic acid
-
Enzyme Inhibitors
-
Piperidines
-
Niacinamide
-
11-beta-Hydroxysteroid Dehydrogenase Type 1