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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Wang, Haofan¹  Byun, Youngjoo¹  Barinka, Cyril²  Pullambhatla, Mrudula¹  Bhang, Hyo-eun C.³  Fox, James J.¹  Lubkowski, Jacek²  Mease, Ronnie C.¹  Pomper, Martin G.^1,3 

[1] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21231 USA

[2] NCI, Ctr Canc Res, Frederick, MD 21702 USA

[3] Johns Hopkins Med Inst, Dept Pharmacol & Mol Sci, Baltimore, MD 21231 USA

关键词: PSMA;    Glutamate carboxypeptidase II;    Molecular imaging;    Radiopharmaceutical;    SPECT;   

DOI  :  10.1016/j.bmcl.2009.10.061

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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