Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1′ side chain

Pavel Majer, Bunda Hin, Doris Stoermer, Jessica Adams, Weizheng Xu, Bridget R. Duvall, Greg Delahanty, Qun Liu, Marigo J. Stathis, Krystyna M. Wozniak, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

Abstract

A series of thiol-based inhibitors containing a benzyl moiety at the P1′ position have been synthesized and tested for their abilities to inhibit glutamate carboxypeptidase II (GCP II). 3-(2-Carboxy-5-mercaptopentyl)- benzoic acid 6c was found to be the most potent inhibitor with an IC 50 value of 15 nM, 6-fold more potent than 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA), a previously discovered, orally active GCP II inhibitor. Subsequent SAR studies have revealed that the phenoxy and phenylsulfanyl analogues of 6c, 3-(1-carboxy-4-mercaptobutoxy)benzoic acid 26a and 3-[(1-carboxy-4-mercaptobutyl)thio]benzoic acid 26b, also possess potent inhibitory activities toward GCP II. In the rat chronic constriction injury (CCI) model of neuropathic pain, compounds 6c and 26a significantly reduced hyperalgesia following oral administration (1.0 mg/kg/day).

Original languageEnglish (US)
Pages (from-to)2876-2885
Number of pages10
JournalJournal of medicinal chemistry
Volume49
Issue number10
DOIs
StatePublished - May 18 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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