Novel Cyclooxygenase-2 Inhibitors: Epileptogenesis

描述（由申请人提供）：在美国，近3%的人口被诊断患有某种形式的癫痫，估计每年的费用为100亿至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危人群（如中风或脑外伤患者）癫痫发展的治疗方法。选择性抑制环氧合酶-2 （COX-2）的新型药物代表了这类重要药物的关键进展。其耐受性的提高使得关节炎等慢性炎症性疾病和包括癌症在内的增殖性疾病得以治疗。包括我们（Hewett）在内的几个实验室最近的研究结果表明，可以开发出对神经元COX-2具有优越活性的选择性抑制剂，用于预防癫痫。我们已经开发了三种新的化学型（吡唑啉类、腙类和乙酰硫化物类），它们具有强效和选择性的COX-2抑制活性。这些化合物的初步研究表明，它们在动物和培养的神经细胞中具有良好的安全性。本提案的具体目标是：短期（12个月）。利用围绕三种新化学型创建的COX-2抑制剂迷你文库，我们将在癫痫发生的动物模型中评估COX-2的抑制作用。基于这些结果，我们将在这些化学型中制备更多新的类似物以进一步评估。利用我们的生物实验和分子建模工具，我们将建立我们的新系列化合物的SAR活性模式。中期。确定一种用于癫痫治疗的临床新药（IND）申请，并进行i期临床研究。根据我们的结果，我们将在美国国立卫生研究院（NIH）和其他机构确定临床合作者，以制定临床测试计划。我们将与一家GMP制造商签订长期合同，生产用于高级临床前研究和IND的材料。成功完成第一阶段的候选人将进一步发展。根据早期研究的结果和公司的需求，第二阶段和第三阶段评估的后期研究可以在内部或与商业伙伴合作完成。

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.