Gavestinel (GV-150,526) was an investigational drug developed by
GlaxoSmithKline for acute
intracerebral hemorrhage, which in 2001 failed to show an effect in what was at the time, the largest clinical trial in
stroke that had been conducted.[1][2]
Gavestinel is an
NMDA antagonist, binding selectively to the
glycine site on the NMDA receptor complex, rather than the
glutamate site many NMDA antagonists bind to.[3][4][5]
Pharmacology and toxicology
N-methyl-D-aspartate (NMDA) receptors are amino acid receptors, overstimulation to which lead to increased intracellular Ca2+ level, and become deleterious to neural cell. In ischaemic or hypoxic conditions such as stroke, the concentration of glutamate in synaptic clefts is increased, and continuously stimulates NMDA receptors. Gavestinel was synthesized by substituting indole-2-carboxylate at the C-3 position with an unsaturated lateral side chain. It binds to NMDA receptor on the glycine site with high affinity, selectivity and a broad time window efficacy, thus gains interests in testing its efficacy in treating stroke. In pre-clinical studies, gavestinel showed no significant side effects on memory, learning, and cardiovascular system, side effects that are very common in NMDA antagonists.[6]
Clinical studies
In phase ΙΙ clinical studies to investigate safety, tolerability of gavestinel, no findings showed that it had significant side effects. The dose determined in phase ΙΙ trials was selected for further phase III trials.[7] Later, however, in two large phase III trials, gavestinel showed no efficacy in treating ischemic stroke.[8]
^Ikonomidou C, Turski L (October 2002). "Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?". The Lancet. Neurology. 1 (6): 383–6.
doi:
10.1016/s1474-4422(02)00164-3.
PMID12849400.
S2CID31477519.
^Hoyte L, Barber PA, Buchan AM, Hill MD (March 2004). "The rise and fall of NMDA antagonists for ischemic stroke". Current Molecular Medicine. 4 (2): 131–6.
doi:
10.2174/1566524043479248.
PMID15032709.