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Bioorg Med Chem Lett. 2010 Jan 1;20(1):392-7. doi: 10.1016/j.bmcl.2009.10.061. Epub 2009 Oct 24.

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

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  • 1Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.


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 20nM. Among them, compound 32d (K(i)=11nM) 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.

Copyright 2009 Elsevier Ltd. All rights reserved.

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