Pre-clinical Development of a Context-Dependent NMADR Neuroprotectant for Treatme

DESCRIPTION provided by applicant Cerebral ischemia is a major cause of death and long term disability with high accompanying social and medical costs Approximately Americans suffer a stroke each year at an estimated annual cost of $ B American Heart Association Heart Disease and Stroke Statistics Update Substantial preclinical data support the use of NMDA receptor antagonists to reduce brain damage caused by cerebral ischemia However to date no drug acting through this target has been successful in clinical trials of cerebral ischemia largely due to two issues i adverse effects that prevented attaining drug levels adequate for efficacy and ii clinical restraints that prevented drug administration within the short time after ischemia required for efficacy We are using a multi pronged strategy to overcome these obstacles in the development of a context dependent pH sensitive NR B subunit selective NMDA receptor antagonist for prophylactic use in subarachnoid hemorrhage SAH SAH patients are at substantial risk of experiencing a stroke like ischemic event four to days after their surgery to coil or clip their aneurysm NR B selective antagonists are intrinsically better tolerated than early generations of non selective NMDA antagonists Furthermore our medicinal chemistry and pharmacology group has discovered and optimized compounds selective for NR B receptor inhibition that are more potent at the interstitial acidic pH characteristic of the penumbral region in focal ischemia than non ischemic tissue More importantly the relative lack of NMDA receptor block in non ischemic healthy tissues at physiological pH minimizes the potential for on target cognitive and psychotomimetic adverse effects that have limited prior drug candidates Because of the context dependent penumbral selective actions of our compounds we anticipate a dramatic improvement in drug tolerability allowing for prophylactic administration prior to ischemia during the days after aneurysm surgery in SAH patients Thus our IND candidate will be available for neuroprotective NMDA receptor block at the site of and earliest onset of secondary ischemia The work proposed here is aimed at identifying a novel neuroprotective agent suitable for prophylactic use by taking advantage of coupling pH dependent receptor block with the intrinsic efficacy and tolerability of NR B selective NMDA receptor blockade Cerebral ischemia describes many conditions in which there is inadequate blood supply to the brain Cerebral ischemia may be caused by stroke traumatic brain injury or may happen during cardiovascular surgery It is a significant cause of death and disability There are no drugs approved that protect brain tissue from ischemia induced damage We propose to develop a novel drug to protect the brain from damage caused by cerebral ischemia