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Issue 10, 2012
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Reduction of acyl glucuronidation in a series of acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors: the discovery of AZD6925

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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

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Publication details

The article was received on 11 Jun 2012, accepted on 10 Aug 2012 and first published on 13 Aug 2012


Article type: Concise Article
DOI: 10.1039/C2MD20154B
Med. Chem. Commun., 2012,3, 1264-1269

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    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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