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    Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3

    Heinrich, D.M. and Flanagan, J.U. and Jamieson, S.M.F. and Silva, S. and Rigoreau, L.J.M. and Trivier, E. and Raynham, T. and Turnbull, Andrew P. and Denny, W.A. (2013) Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3. European Journal of Medicinal Chemistry 62 , pp. 738-744. ISSN 0223-5234.

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    Abstract

    High expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes. We describe here a series of (piperidinosulfonamidophenyl)pyrrolidin-2-ones as potent (<100 nM) and isoform-selective non-carboxylate inhibitors of AKR1C3. Structure-activity relationships identified the sulfonamide was critical, and a crystal structure showed the 2-pyrrolidinone does not interact directly with residues in the oxyanion hole. Variations in the position, co-planarity or electronic nature of the pyrrolidinone ring severely diminished activity, as did altering the size or polarity of the piperidino ring. There was a broad correlation between the enzyme potencies of the compounds and their effectiveness at inhibiting AKR1C3 activity in cells.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): aldo-keto reductase, inhibitor, crystal structure, computer aided drug design
    School: School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 11 Feb 2013 10:31
    Last Modified: 27 Jun 2013 14:31
    URI: https://eprints.bbk.ac.uk/id/eprint/6142

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