GV-196771A

Neuroprotective potential of ionotropic glutamate receptor antagonists

From the therapeutic point of view, the real challenge is not only to improve the symptoms, but to interfere with the pathomechanism of the disease. That is why a considerable interest has recently been devoted to developing glutamate receptor antagonists (mainly of the NMDA type) for acute and chronic neurodegeneration. Developing such a treatment that slows down the progression of the disease is extremely time and cost consuming. At present there is consensus that competitive NMDA receptor antagonists will not find therapeutic applications, in contrast to agents acting at the glycine(B) site, or channel blockers. Recently, at least seven glycine(B) antagonists (e.g. ACEA 1021, GV-150526, GV-196771A, ZD-9379, MRZ 2/576) and over 10 NMDA channel blockers (e.g. Remacemide, ARL-15896AR, HU-211, ADCI, CNS-5161, Neramexane-MRZ 2/579) have been under development, most of them as neuroprotective agents for acute (stroke, trauma) or chronic insult (e.g. Huntington's or Alzheimer's disease). Several substances selective for NR2B NMDA receptor subtypes such as eliprodil, CP-101606 and Ro-25-6981 have been claimed to have a good neuroprotective profile. This presentation is an attempt to critically review preclinical and scarce clinical experience in the development of new NMDA receptor antagonists as neuroprotective agents according to the following scheme: rational, preclinical findings in animal models and finally clinical experience if available. The general impression is that NMDA receptor antagonists may find use in chronic type of neurodegeneration while AMPA antagonists seem to show better promise in acute insult.

Novel stereocontrolled addition of allylmetal reagents to alpha-imino esters: efficient synthesis of chiral tetrahydroquinoline derivatives

To prepare in multigram scale new antagonists of the glycine binding site associated to the NMDA receptor, an efficient distereoselective route was set up. The addition of suitable allyltin reagents to chiral N-aryl alpha-imino esters (R-(+)-tert-butyl lactate used as chiral auxiliary), gave the corresponding alpha amino acid-type derivative in high chemical yield and optical purity. This allylation reaction represents a novel example of efficient long-range stereodifferentiation process. In the last part of the synthesis, a regioselective Heck-type cyclization reaction enabled preparation of the target tetrasubstituted exocycle and trisubtituted endocycle double bond derivatives.

Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A

Central sensitization is a condition of enhanced excitability of spinal cord neurons that contributes to the exaggerated pain sensation associated with chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this hypothesis by characterizing in vitro and in vivo a novel antagonist of the NMDA receptor acting on its glycine site, GV196771A. GV196771A exhibited an elevated affinity for the NMDA glycine binding site in rat cerebral cortex membranes (pKi = 7.56). Moreover, GV196771A competitively and potently antagonized the activation of NMDA receptors produced by glycine in the presence of NMDA in primary cultures of cortical, spinal, and hippocampal neurons (pKB = 7.46, 8. 04, and 7.86, respectively). In isolated baby rat spinal cords, 10 microM GV196771A depressed wind-up, an electrical correlate of central sensitization. The antihyperalgesic properties of GV196771A were studied in a model of chronic constriction injury (CCI) of the rat sciatic nerve and in the mice formalin test. In the CCI model GV196771A (3 mg/kg twice a day p.o.), administered before and then for 10 days after nerve ligature, blocked the development of thermal hyperalgesia. Moreover, GV196771A (1-10 mg/kg p.o.) reversed the hyperalgesia when tested after the establishment of the CCI-induced hyperalgesia. In the formalin test GV196771A (0.1-10 mg/kg p.o.) dose-dependently reduced the duration of the licking time of the late phase. These antihyperalgesic properties were not accompanied by development of tolerance. These observations strengthen the view that NMDA receptors play a key role in the events underlying plastic phenomena, including hyperalgesia. Moreover, antagonists of the NMDA glycine site receptor could represent a new analgesic class, effective in conditions not sensitive to classical opioids.

A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain

Background: Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 is a selective antagonist of the glycine-binding site of the NMDA ionophore.
Objective: To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study.
Methods: With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging > or =30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study.
Results: There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%).
Conclusions: Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.

First time in human for GV196771: interspecies scaling applied on dose selection

The utility of interspecies scaling in early drug development has been extensively debated. The authors discuss the dose selection strategy for a first time into man (FTIM) study for GV196771, a new glycine antagonist, using techniques of interspecies scaling. The FTIM dose selection strategy was based on predicted plasma profiles of GV196771 in humans using allometric scaling and considerations of safety and pharmacological activity in animals. Allometric techniques were first retrospectively applied to data obtained in humans and animals for GV150526, a glycine antagonist with similar pharmacokinetic characteristics to GV196771. GV196771 and GV150526 are extensively protein bound; thus, protein binding differences among species were considered in the scaling. Using the scaled pharmacokinetic parameters, compartmental modeling was performed to prospectively simulate concentration profiles for the oral administration of GV196771. This article will discuss the outcome of the prospective dose selection strategy for GV196771 compared to the actual concentration profiles observed in the FTIM study.