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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)

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journal contribution
posted on 28.06.2012, 00:00 authored by James S. Scott, 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
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.