Delving into the Latest Updates on GPI-5232 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

GPI 5232

Target

PSMA

Mechanism

PSMA inhibitors(Prostate-specific membrane antigen inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Diabetic Neuropathies

Originator Organization

MGI GP, Inc.

Active Organization-

Inactive Organization

MGI GP, Inc.

Drug Highest PhaseDiscontinuedPreclinical

First Approval Date-

Regulation-

Long-term individual housing increases aggressive behavior in mice, a condition termed isolation-induced aggression; this aggressiveness is reduced by some antidepressants and anxiolytics. NMDA antagonists also inhibit isolation-induced aggression in mice. The enzyme N-acetylated-alpha-linked acidic dipeptidase (NAALADase) hydrolyzes the neurotransmitter N-acetylaspartylglutamate (NAAG) to form glutamate and N-acetylaspartate; NAAG acts as a partial NMDA agonist as well as a full agonist at the presynaptic metabotropic glutamate receptor 3 (mGluR3), where it acts to reduce glutamate release.

OBJECTIVE:

We postulated that NAALADase inhibition would reduce isolation-induced aggression in mice.

METHODS:

We tested whether acute exposure to the NAALADase inhibitor 2-[[hydroxy[2,3,4,5,6-pentafluorophenyl)methyl]phosphinyl]methyl] pentanedioic acid (GPI-5232), administered 30 min prior to a social interaction test, would inhibit aggressive behavior in SJL mice that had been individually housed long term.

RESULTS:

Administration of GPI-5232 (30 mg/kg, IP) inhibited initiation of aggressive behavior, indicated by greater latencies to display tail-rattling, attack and biting, and by fewer mice initiating aggressive behavior, compared to mice that received vehicle. In addition, GPI-5232 treated mice had fewer tail-rattling responses to a non-aggressive conspecific.

CONCLUSIONS:

The effectiveness of GPI-5232 in this animal model suggests that NAALADase inhibition may be a novel therapeutic approach to reduce or inhibit heightened aggressiveness, and possibly to treat aggressive behavior associated with psychiatric disorders.

01 Feb 2002·Journal of the neurological sciencesQ4 · MEDICINE

GCPII (NAALADase) inhibition prevents long-term diabetic neuropathy in type 1 diabetic BB/Wor rats

Q4 · MEDICINE

Article

Author: P.F Jackson ; K.M Wozniak ; A.A.F Sima ; W Zhang ; Y Murakawa ; B Slusher ; T Tsukamoto

AIMS/HYPOTHESIS:

Hyperglutamatergic activity induced by ischemia is believed to underlie neuronal damage in a variety of neurological disorders, including neuropathic pain. Since ischemia is believed to be a prominent mechanism involved in diabetic polyneuropathy (DPN), we investigated the effect of the glutamate carboxypeptidase II (GCPII, EC #3.4-17.21; previously termed NAALADase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG to NAA and glutamate, on the development of DPN in type 1 diabetic BB/Wor rats.

METHODS:

Diabetic animals were treated with 10 mg/kg/day i.p. of the selective GCPII inhibitor GPI-5232 from onset of diabetes for 6 months. Hyperalgesia to thermal stimulation and nerve conduction velocity (NCV) were measured monthly. The effect on structural DPN was assessed by scoring of single, teased myelinated fibers, myelinated fiber morphometry and ultrastructural examination of C-fibers at 6 months.

RESULTS:

GCPII inhibition showed significant but partial effects on hyperalgesia (p<0.001), nerve conduction slowing (p<0.01) axonal and nodal structural changes (p<0.001), small myelinated fiber atrophy, and degenerative changes of C-fibers.

CONCLUSIONS:

GCPII inhibition has beneficial effects on hyperalgesia, nerve function, and structural degenerative changes in DPN, which are likely mediated by inhibition of ischemia-induced glutamate release.

01 Oct 2001·The Journal of pharmacology and experimental therapeutics

Electroencephalogram analysis and neuroprotective profile of the N-acetylated-alpha-linked acidic dipeptidase inhibitor, GPI5232, in normal and brain-injured rats.

Article

Author: Williams, A J ; Tortella, F C ; Lu, X M ; Slusher, B

We have evaluated the effects of the N-acetylated-alpha-linked acidic dipeptidase (NAALADase) inhibitor, GPI5232 [2-[(pentafluorophenylmethyl)hydroxyphosphinyl]methyl)-pentanedioic acid], to not only decrease brain injury but also to alter the inherent electroencephalographic (EEG) changes observed in a rat model of transient middle cerebral artery occlusion (MCAo). Continuous i.v. infusion of GPI5232 starting 1 h after injury resulted in more than a 50% reduction in brain infarct volume caused by 2 h of MCAo. This effect was dose-dependent and significant even when first treatment was delayed for 2 h post-MCAo. At 24 h post-MCAo, EEG spectral analysis of the injured hemisphere revealed functional improvement in GPI5232-treated rats. Significant recovery in high-frequency EEG power (8-30 Hz) was measured in GPI5232-treated animals in both parietal and temporal brain regions but not in vehicle-treated animals. MCAo-injured rats were also predisposed to developing cortical brain seizures, and GPI5232-treated rats had significantly fewer brain seizures than vehicle-treated animals. In separate experiments, acute high doses of GPI5232 in normal rats did not significantly alter EEG brain activity as evaluated by spectral analysis and did not produce any signs of seizure activity or behavioral abnormalities. These results show GPI5232 to be an effective neuroprotective treatment when given postinjury by reducing brain infarction and ameliorating the pathological EEG associated with focal brain ischemia.

100 Deals associated with GPI-5232

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