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Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies

  1. Author:
    Wang, H. F.
    Byun, Y.
    Barinka, C.
    Pullambhatla, M.
    Bhang, H. E. C.
    Fox, J. J.
    Lubkowski, J.
    Mease, R. C.
    Pomper, M. G.

  2. Author Address

    [Wang, Haofan; Byun, Youngjoo; Pullambhatla, Mrudula; Fox, James J.; Mease, Ronnie C.; Pomper, Martin G.] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21231 USA. [Barinka, Cyril; Lubkowski, Jacek] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Bhang, Hyo-eun C.; Pomper, Martin G.] Johns Hopkins Med Inst, Dept Pharmacol & Mol Sci, Baltimore, MD 21231 USA.;Pomper, MG, Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21231 USA.;mpomper@jhmi.edu
    1. Year: 2010
    2. Date: Jan
  2. Journal: Bioorganic & Medicinal Chemistry Letters
    1. 20
    2. 1
    3. Pages: 392-397
  4. Type of Article: Article
  5. ISSN: 0960-894X
  1. Abstract:

    We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1' site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with K-i values below 20 nM. Among them, compound 32d (K-i = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1' pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d. (C) 2009 Elsevier Ltd. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.bmcl.2009.10.061
  3. View record in Web of Science®
  4. WOS: 000272935600088

Library Notes

  1. Fiscal Year: FY2009-2010
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