SBIR-STTR Award

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.

Thesaurus Terms:
drug design /synthesis /production, enzyme inhibitor, nervous system disorder chemotherapy, neuroprotectant, prostaglandin endoperoxide synthase Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, biotherapeutic agent, cerebral ischemia /hypoxia, drug discovery /isolation, glutamate receptor, heterocyclic compound, neuropharmacology, nonsteroidal antiinflammatory agent, stroke laboratory mouse, tissue /cell culture

Strategies aimed at limiting and repairing the damage attributed to oxidative stress may slow the advance of numerous age-related diseases. Numerous studies indicate that the enzyme cyclooxygenase-2 (COX-2) is induced by oxidative stress, contributes to oxidative stress, and promotes subsequent neuronal injury. In this application we propose continuation of our studies carried out under a Phase I SBIR grant to identify suitable COX-2 inhibitor new chemical entities (NCEs) to address oxidative stress-induced damage to the neuronal cells. The overall aim of the proposed grant application is to advance our initial discovery of a novel activity toward a clinical application of these NCEs. During the Phase I grant period, we established that certain Onconova COX-2 inhibitors (analogs of the ON 09 and ON 26 series), but not other commercially available COXibs, prevented oxidative stress-induced programmed neuronal cell death in vitro. Additionally, we demonstrated that systemic administration of naproxen, a non-selective COX inhibitor, partially but potently prevented the injury induced by direct intrahippocampal injection of the glutamate agonist, N-methyl- D-Aspartate (NMDA). Thus, the objectives of this Phase II research plan of study are as follows: 1) to determine the therapeutic potential of a novel COX-2 compound (ON 26040) against oxidative stress-induced neuronal injury in vivo. Studies will be undertaken to identify whether ON 26040 can effectively prevent injury induced by a) direct hippocampal injection of NMDA and/or b) striatal injury associated with systemic injection of 3-nitroproprionic acid; 2) To identify the molecular mechanism mediating the neuroprotective effects of ON 26040 in vitro. Studies will utilize the HCA injury model to analyze COX-dependent and/or -independent mechanisms of death suppression. Specifically, the ability of ON 26040 to modulate the Akt/PKB and extracellular signal-regulated kinase (ERK) signal transduction pathways will be explored; 3) to develop a pre-clinical safety and pharmacology profile of ON 26040 for regulatory submission. Studies will involve short term (7 day) and long term (28 day) repeat dose toxicology studies in rats and dogs and complete pharmacological assessment in both in vitro and in vivo models (rodents and canines). Specifically, this complete pre-clinical evaluation package will permit filing of an Investigational New Drug (ND) application for human clinical studies; and 4) To develop a clinical Phase I protocol for testing the safety of ON 26040 in human volunteers. This will involve selection of appropriate clinical therapeutic indication based on animal models and the establishment of dosing, testing and monitoring guidelines for an FDA and IRB approved study to be conducted following the completion of studies proposed herein