Up-regulation of COX-2 has also been reported to occur in human brains following a lethal cerebral ischemic insult and selective inhibition of COX-2 has been demonstrated to be neuroprotective in animal models. In addition, there has been a voluminous literature that suggests that cyclooxygenase-2 (COX-2) may contribute to neuronal injury in various neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's and Alzheimer's disease. Indeed, numerous studies on the long-term use of NSAID's have demonstrated the improvement or a decrease in the potential of Alzheimer's disease (AD). The decrease in undesirable GI side effects of selective COX-2 has stimulated long-term clinical evaluation studies of current marketed COX-2 inhibitor for AD. We have developed a novel chemotype (Onconova compounds ON 09** Series) with potent and selective COX-2 inhibitory activity. In collaboration with Dr. Sandra Hewett at the University Connecticut Health Center, these compounds are now being applied for various indications including prevention of cancer, inflammation and CNS injury.
The specific aims are as follows: Short term; 6 months - Employing the mini library of COX-2 inhibitors created around the new chemotype identified by Onconova, we will evaluate whether inhibition of COX-2 by these drugs in Dr. Hewett's CNS model will be neuroprotective. Specifically, studies will be undertaken to determine the therapeutic potential of these novel COX-2 compounds against NMDA-induced neuronal injury (excitotoxicity) in mixed cortical cell cultures as excitotoxicity has been implicated in the pathogenesis of brain injury triggered by hypoxic-ischemia insults as well as AD. Based on these results, we will employ Structure Activity Relationship (SAR) to prepare additional novel COX-2 compounds for evaluation. We will establish a SAR pattern of activity with our novel series of compounds. Intermediate term - Effective demonstration of neuroprotection in the in vitro model will aid in the identification of interesting and active compounds for in vivo animal studies of neuronal injury associated with over-activation of glutamate receptors, including AD and stroke. Following the identification of a lead compound, production of large quantities of the compound for these studies will be undertaken. Long term - A candidate that successfully completes Phase 1 will be further developed. The later studies for Phase 2 and Phase 3 evaluations will be carried out internally or with a commercial partner, based on the needs of the company.
