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

Haofan Wang; Youngjoo Byun; Cyril Barinka; Mrudula Pullambhatla; Hyo eun C. Bhang; James J. Fox; Jacek Lubkowski; Ronnie C. Mease; Martin G. Pomper

doi:10.1016/j.bmcl.2009.10.061

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

Haofan Wang, Youngjoo Byun, Cyril Barinka, Mrudula Pullambhatla, Hyo eun C. Bhang, James J. Fox, Jacek Lubkowski, Ronnie C. Mease, Martin G. Pomper

School of Medicine

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57 Scopus citations

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.

Original language	English (US)
Pages (from-to)	392-397
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2009.10.061
State	Published - Jan 1 2010

Keywords

Glutamate carboxypeptidase II
Molecular imaging
PSMA
Radiopharmaceutical
SPECT

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2009.10.061

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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 Ki values below 20 nM. Among them, compound 32d (Ki = 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.",

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AU - Wang, Haofan

AU - Byun, Youngjoo

AU - Barinka, Cyril

AU - Pullambhatla, Mrudula

AU - Bhang, Hyo eun C.

AU - Fox, James J.

AU - Lubkowski, Jacek

AU - Mease, Ronnie C.

AU - Pomper, Martin G.

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AB - 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 Ki values below 20 nM. Among them, compound 32d (Ki = 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.

KW - Glutamate carboxypeptidase II

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KW - Radiopharmaceutical

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

Abstract

Keywords

ASJC Scopus subject areas

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