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

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 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.

SUBMITTER: Wang H

PROVIDER: S-EPMC2818328 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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

Wang Haofan H Byun Youngjoo Y Barinka Cyril C Pullambhatla Mrudula M Bhang Hyo-Eun C HE Fox James J JJ Lubkowski Jacek J Mease Ronnie C RC Pomper Martin G MG

Bioorganic & medicinal chemistry letters 20091024 1

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' pha ...[more]

PMID: 19897367

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