Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffolds.

A series of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors have been synthesized with either a 3-(mercaptomethyl)benzoic acid or 2-(2-mercaptoethyl)benzoic acid scaffold. Potent inhibitors were identified from each of the two scaffolds with IC(50) values in the single-digit nanomolar range, including 2-(3-carboxybenzyloxy)-5-(mercaptomethyl)benzoic acid 27c and 3-(2-mercaptoethyl)biphenyl-2,3'-dicarboxylic acid 35c. Compound 35c was found to be metabolically stable and selective over a number of targets related to glutamate-mediated neurotransmission. Furthermore, compound 35c was found to be orally available in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

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

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).

Synthesis and biodistribution of (11)C-GW7845, a positron-emitting agonist for peroxisome proliferator-activated receptor-{gamma}.

UNLABELLED: The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist (11)C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester) ((11)C-compound 1). PPARgamma is a member of a family of nuclear receptors that plays a central role in the control of lipid and glucose metabolism. Compound 1 is an analog of tyrosine (inhibitor constant, 3.7 nmol/L), which is an inhibitor of experimental mammary carcinogenesis. METHODS: Protection of the carboxylic acid moiety of compound 1 was effected by treatment with N,N-dimethylformamide di-tert-butyl acetal to provide compound 2. Hydrolysis of the carbomethoxy group of compound 2 provided the benzoic acid (compound 3) that served as an immediate precursor to radiolabeling. Compound 3 underwent treatment with (11)C-methyl iodide followed by high-performance liquid chromatography to produce a radioactive peak sample that coeluted with a standard sample of compound 1. Analysis of biodistribution was undertaken by injecting male CD-1 mice via the tail vein with 6.03 MBq (163 microCi, 2.55 microg/kg) of (11)C-compound 1. To determine the tumor uptake of the radiotracer, 6 female SCID mice bearing MCF-7 xenografts were injected via the tail vein with 10.5 MBq (283 microCi, 0.235 microg/kg) of (11)C-compound 1. RESULTS: (11)C-Compound 1 was synthesized at an 8% radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/micromol (33,024 mCi/micromol; n = 6) at the end of synthesis. Spleen (target)-to-muscle uptake and tumor-to-muscle uptake ratios were 3.1 and 1.5, respectively, but this uptake could not be blocked with unlabeled compound 1 at 2 mg/kg. CONCLUSION: Further structural modification, perhaps to generate a less lipophilic tyrosine analog, will be necessary to enable receptor-mediated PPARgamma imaging by this class of agents.

Synthesis and biological evaluation of hydroxamate-Based inhibitors of glutamate carboxypeptidase II.

A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1' residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC(50) value of 220nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.

Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: discovery of an orally active GCP II inhibitor.

A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.