Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4‑[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)

Inhibition of 11β-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...

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Veröffentlicht in:	Journal of medicinal chemistry 2012-11, Vol.55 (22), p.10136-10147
Hauptverfasser:	Scott, James S, deSchoolmeester, Joanne, Kilgour, Elaine, Mayers, Rachel M, Packer, Martin J, Hargreaves, David, Gerhardt, Stefan, Ogg, Derek J, Rees, Amanda, Selmi, Nidhal, Stocker, Andrew, Swales, John G, Whittamore, Paul R. O
Format:	Artikel
Sprache:	eng
Schlagworte:	11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism Adipose Tissue - drug effects Adipose Tissue - enzymology Animals Benzoates - chemical synthesis Benzoates - pharmacokinetics Benzoates - pharmacology Dogs Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Glucuronides - chemistry Glucuronides - metabolism Guinea Pigs Humans Liver - drug effects Liver - enzymology Macaca fascicularis Mice Models, Molecular Molecular Structure Protein Conformation Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Pyridines - chemistry Rats Rats, Wistar Structure-Activity Relationship Substrate Specificity
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