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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)392-397
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number1
DOIs
StatePublished - 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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