Issue 10, 2012

Reduction of acyl glucuronidation in a series of acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors: the discovery of AZD6925

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 optimisation of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD6925 (11). A central aim of this optimisation campaign was the modulation of clearance mechanism to reduce the extent of acyl glucuronidation. This was achieved by modulation of the acid substructure together with a redistribution of lipophilicity in order to achieve the desired profile.

Graphical abstract: Reduction of acyl glucuronidation in a series of acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors: the discovery of AZD6925

Supplementary files

Article information

Article type
Concise Article
Submitted
11 Jun 2012
Accepted
10 Aug 2012
First published
13 Aug 2012

Med. Chem. Commun., 2012,3, 1264-1269

Reduction of acyl glucuronidation in a series of acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors: the discovery of AZD6925

J. S. Scott, P. Barton, S. N. L. Bennett, J. deSchoolmeester, L. Godfrey, E. Kilgour, R. M. Mayers, M. J. Packer, A. Rees, P. Schofield, N. Selmi, J. G. Swales and P. R. O. Whittamore, Med. Chem. Commun., 2012, 3, 1264 DOI: 10.1039/C2MD20154B

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