2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2012 Nov 26;55(22):10136-47. doi: 10.1021/jm301252n.
James S Scott 1,  Joanne deSchoolmeester,  Elaine Kilgour,  Rachel M Mayers,  Martin J Packer,  David Hargreaves,  Stefan Gerhardt,  Derek J Ogg,  Amanda Rees,  Nidhal Selmi,  Andrew Stocker,  John G Swales,  Paul R O Whittamore
Affiliations

Affiliation

  • 1 Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside , Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. jamie.scott@astrazeneca.com
PMID: 23088558 DOI: 10.1021/jm301252n
Abstract

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 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.

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