title: Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1' side chain.
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).
authors: MGI Pharma, Inc., 6611 Tributary Street, Baltimore, Maryland 21224, USA.
authors: Pavel
authors: P
authors: Majer
authors: Bunda
authors: B
authors: Hin
authors: Doris
authors: D
authors: Stoermer
authors: Jessica
authors: J
authors: Adams
authors: Weizheng
authors: W
authors: Xu
authors: Bridget R
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authors: Duvall
authors: Greg
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authors: Delahanty
authors: Qun
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authors: Liu
authors: Marigo J
authors: MJ
authors: Stathis
authors: Krystyna M
authors: KM
authors: Wozniak
authors: Barbara S
authors: BS
authors: Slusher
authors: Takashi
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authors: Tsukamoto