irampanel and Stroke

The oxazole derivative, irampanel, a non-competitive AMPA receptor antagonist, is under development by Boehringer Ingelheim for the potential treatment of stroke [329079]. Phase I/IIa trials for stroke had been initiated by July 2000 [374144]. Phase II trials were ongoing in April 2001 [407163]; in April 2002, however, the drug did not appear on the company's research and development pipeline [446554], and a company spokesperson declined to confirm its current status [450591]. The compound was also originally under investigation for other neurological disorders, including epilepsy and pain [329079], although by October 1999, development was only ongoing for stroke [346080].

Topics: Animals; Clinical Trials, Phase I as Topic; Disease Models, Animal; Humans; Oxadiazoles; Receptors, AMPA; Stroke

Ischaemic stroke of the brain accounts for about one third of all deaths in industrialized countries. Many of the patients who survive are severily impaired. Thus, there is an enormous need for pharmacotherapy for the treatment of ischaemic stroke. Why is such a treatment not available yet? Are the pathophysiological sequelae of brain ischaemia not well understood? Have there been no attempts for clinical development of neuroprotective drugs? Everyone who is engaged in stroke research knows that the opposite is true: The cellular processes occuring after brain ischaemia have been studied for a long time, and we have a thorough understanding of the cellular processes which are involved. Many compounds underwent clinical trials, but most of them failed. One hypothesis to explain this disappointing fact might be that the cellular consequences of stroke are manyfold, but that the clinically tested compounds were selective for only one molecular mechanism. The aim of this review is to give a summary of the pathophysiological mechanisms which occur during and after an ischaemic stroke, and to comment on the preclinical studies where multiple disease-related mechanisms were targeted pharmacologically. Moreover, a novel class of neuroprotective compounds, the oxadiazole derivatives, will be presented. Compounds of this chemical class target two key mechanisms which are important for the pathophysiology of stroke, namely voltage-gated sodium channels, as well as glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype.

Topics: Brain Ischemia; Drug Evaluation, Preclinical; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Fibrinolytic Agents; Humans; Neuroprotective Agents; Oxadiazoles; Receptors, AMPA; Stroke

Topics: Amyotrophic Lateral Sclerosis; Analgesics; Anticonvulsants; Epilepsy; Humans; Ion Channel Gating; Models, Molecular; Mutation; Nerve Tissue Proteins; Neuroprotective Agents; Protein Binding; Sodium Channel Blockers; Sodium Channels; Stroke