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

被引：70

作者：

Wang, Haofan ^{[1
]}

Byun, Youngjoo ^{[1
]}

Barinka, Cyril ^{[2
]}

Pullambhatla, Mrudula ^{[1
]}

Bhang, Hyo-eun C. ^{[3
]}

Fox, James J. ^{[1
]}

Lubkowski, Jacek ^{[2
]}

Mease, Ronnie C. ^{[1
]}

Pomper, Martin G. ^{[1
,3
]}

机构：

[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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 01期

基金：

美国国家卫生研究院;

关键词：

PSMA; Glutamate carboxypeptidase II; Molecular imaging; Radiopharmaceutical; SPECT; GLUTAMATE-CARBOXYPEPTIDASE-II; NAAG PEPTIDASE INHIBITORS; ISCHEMIC BRAIN-INJURY; MEMBRANE ANTIGEN; PROSTATE-CANCER; N-ACETYLASPARTYLGLUTAMATE; MONOCLONAL-ANTIBODIES; MODELS; SCHIZOPHRENIA; NEUROPATHY;

D O I：

10.1016/j.bmcl.2009.10.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：392 / 397

页数：6

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