Pre-clinical Developmemt of a Novel COX-2 Inhibitor

新型 COX-2 抑制剂的临床前开发

• 批准号: 6644677
• 负责人: STANLEY C BELL
• 金额: $ 10万
• 依托单位: ONCONOVA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6644677
• 关键词: antineoplastics; apoptosis; breast neoplasms; chemical structure function; chemical synthesis; colorectal neoplasms; drug design /synthesis /production; enzyme inhibitors; nonsteroidal antiinflammatory agent; prostaglandin endoperoxide synthase; prostate neoplasms; pyrazoles

DESCRIPTION (provided by applicant): Up-regulation of COX-2 has been reported to occur in cancer cells and selective inhibition of COX-2 has been demonstrated to reduce cancer cell growth in animal models. In addition, there has been a voluminous literature that suggests that cyclooxygenase-2 (COX-2) may contribute to cancer cell growth in various types of cancer including colon and lung carcinomas. Indeed, numerous studies on the long-term use of NSAIDs have demonstrated the improvement or a decrease in the potential of cancer. 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 cancer. We have developed a novel chemotype (Onconova compounds ON 09** Series) with potent and selective COX-2 inhibitory activity. In collaboration with Dr. E. Premkumar Reddy, at The Fels Institute for Cancer Research, Temple University, these compounds are now being applied for various indications including prevention of cancer and inflammation. 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 the level of inhibition of COX-2 by these drugs in Dr. Reddy's enzymatic assay model. Specifically, studies will be undertaken to determine the therapeutic potential of these novel COX-2 compounds against breast and colon cancer. 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 cancer cell apoptosis in the in vitro model will aid in the identification of interesting and active compounds for in vivo animal studies of colorectal, breast and prostate cancer. 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.

描述（由申请人提供）：据报道，癌细胞中出现COX-2的上调，并且在动物模型中选择性抑制COX-2已被证明可以减少癌细胞的生长。此外，大量文献表明环氧合酶-2 (COX-2) 可能有助于多种癌症（包括结肠癌和肺癌）中的癌细胞生长。事实上，大量关于长期使用非甾体抗炎药的研究已经证明可以改善或降低患癌症的可能性。选择性 COX-2 减少不良胃肠道副作用，刺激了对目前市售的 COX-2 癌症抑制剂的长期临床评估研究。我们开发了一种新型化学型（Onconova 化合物 ON 09** 系列），具有有效且选择性的 COX-2 抑制活性。与天普大学菲尔斯癌症研究所的 E. Premkumar Reddy 博士合作，这些化合物现在被应用于各种适应症，包括预防癌症和炎症。具体目标如下： 短期； 6 个月 - 采用围绕 Onconova 确定的新化学型创建的 COX-2 抑制剂迷你库，我们将在 Reddy 博士的酶测定模型中评估这些药物对 COX-2 的抑制水平。具体来说，将进行研究以确定这些新型 COX-2 化合物对乳腺癌和结肠癌的治疗潜力。基于这些结果，我们将利用构效关系（SAR）来制备其他新型COX-2化合物进行评估。我们将用我们的新型化合物系列建立活性SAR模式。中期 - 在体外模型中有效证明癌细胞凋亡将有助于鉴定用于结肠直肠癌、乳腺癌和前列腺癌的体内动物研究的有趣且活性的化合物。在鉴定出先导化合物后，将开始生产大量用于这些研究的化合物。长期 - 成功完成第一阶段的候选人将得到进一步发展。后期的第二阶段和第三阶段评估研究将根据公司的需求在内部或与商业合作伙伴一起进行。