Novel acidic 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).
J Med Chem
; 55(22): 10136-47, 2012 Nov 26.
Article
in En
| MEDLINE
| ID: mdl-23088558
ABSTRACT
Inhibition of 11ß-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazoles
/
Pyridines
/
Benzoates
/
Glucuronides
/
11-beta-Hydroxysteroid Dehydrogenase Type 1
/
Enzyme Inhibitors
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2012
Document type:
Article
Affiliation country:
United kingdom