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)

  • J Med Chem. 2012 Jun 28;55(12):5951-64. doi: 10.1021/jm300592r.
James S Scott  1 ,  Suzanne S Bowker ,  Joanne Deschoolmeester ,  Stefan Gerhardt ,  David Hargreaves ,  Elaine Kilgour ,  Adele Lloyd ,  Rachel M Mayers ,  William McCoull ,  Nicholas J Newcombe ,  Derek Ogg ,  Martin J Packer ,  Amanda Rees ,  John Revill ,  Paul Schofield ,  Nidhal Selmi ,  John G Swales ,  Paul R O Whittamore
Affiliations
  • 1. Cardiovascular and Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. [email protected]
PMID: 22691057 DOI: 10.1021/jm300592r
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.

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