Novel Cyclooxygenase-2 Inhibitors: Epileptogenesis

描述（由申请人提供）：美国近3%的人口被诊断患有某种形式的癫痫，估计每年花费超过120亿美元。癫痫领域转化研究的一个主要目标是开发预防高风险个体（如中风或脑外伤患者）癫痫发展的疗法。选择性抑制环氧合酶-2（考克斯-2）的新型药物代表了这类重要药物的关键进展。其耐受性的改善允许管理慢性炎症性疾病，如关节炎和增殖性疾病，包括癌症。最近的结果，从几个实验室，包括我们的（休伊特）现在表明，选择性抑制剂与上级活动对神经元考克斯-2可以开发用于预防癫痫。我们已经开发了三种新的化学型（吡唑啉，腙和乙酰硫醚）具有有效的和选择性的考克斯-2抑制活性。这些化合物的初步研究已证明在动物和培养的神经元细胞中具有良好的安全性。该提案的具体目标是：短期（12个月）。利用围绕三种新化学型创建的考克斯-2抑制剂的迷你文库，我们将评估考克斯-2在癫痫发生动物模型中的抑制。基于这些结果，我们将在这些化学型中制备额外的新类似物以供进一步评估。使用我们的生物测定和分子建模工具，我们将用我们的新系列化合物建立活性的SAR模式。中期。确定新药临床试验（IND）申请的候选药物，以进行1期癫痫治疗研究。根据我们的研究结果，我们将确定美国国立卫生研究院（NIH）和其他机构的临床合作者，以制定临床测试计划。我们将与GMP生产商签订合同，生产用于高级临床前研究和IND的材料。成功完成第1阶段的候选人将得到进一步发展。根据早期研究的结果和公司的需求，第2阶段和第3阶段评估的后期研究可以在内部或与商业合作伙伴进行。

DESCRIPTION (provided by applicant): Nearly 3% of the population in the United States has been diagnosed with some form of epilepsy at an estimated annual cost of >$12 billion. A major goal of translational research in the field of epilepsy is to develop therapies that prevent epilepsy development in high-risk individuals, such as stroke or brain trauma patients. Novel drugs that selectively inhibit cyclooxygenase-2 (COX-2) represent a key advancement in this important class of drugs. Their improved tolerability has allowed management of chronic inflammatory diseases like arthritis and proliferative disorders including cancer. Recent results from several laboratories including our's (Hewett) now suggest that selective inhibitors with superior activity against neuronal COX-2 can be developed for the prevention of epilepsy. We have developed three novel chemotypes (pyrazolines, hydrazones and acetyl sulfides) with potent and selective COX-2 inhibitory activity. Preliminary work with these compounds has demonstrated a good safety profile in animals and in neuronal cells in culture. The Specific Aims of this proposal are: Short term (12 months). Employing the mini library of COX- 2 inhibitors created around three new chemotypes, we will evaluate the inhibition of COX-2 in an animal model of epileptogenesis. Based on these results, we will prepare additional novel analogs within these chemotypes for further evaluation. Using our biological assay and tools of molecular modeling, we will establish a SAR pattern of activity with our novel series of compounds. Intermediate term. Identify a candidate for Investigational New Drug (IND) application leading to Phase 1 studies for the treatment of epilepsy. Based on our results, we will identify clinical collaborators at the National Institutes of Health (NIH) and other institutions to develop a clinical testing plan. We will contract with a GMP manufacturer to produce material for advanced pre-clinical studies and the IND. Long term. A candidate that successfully completes Phase 1 will be further developed. The later studies for Phase 2 and Phase 3 evaluations can be earned out internally or with a commercial partner, depending on the results of the early studies and the needs of the company.