"Discovery and Development of Anti-Diabetic Drugs."

描述(由申请人提供)：这是NIH第二阶段SBIR续展申请的重新提交，旨在开发和优化能够刺激IRS2为治疗II型糖尿病奠定基础的化合物。如果成功，这种化合物也可能对I型糖尿病患者的一部分患者的治疗有用。这项建议的总体目标是对HPRL科学家已经确定的激活哺乳动物细胞中胰岛素信号转导级联的IRS2分支的新分子实体进行先导优化研究。NIH SBIR资金支持将用于豪西药物研究实验室(以下简称“HPRL”)的重点研究，以进一步开发在波士顿儿童医院、哈佛医学院的莫里斯·怀特博士和乔斯林糖尿病中心的研究人员的实验室中取得的初步发现，以便将来商业化。这些发现已被授权给HPRL用于治疗应用。激活胰岛素介导的信号转导级联的IRS2分支的化合物已经通过高通量筛选(HTS)使用靶蛋白特异性细胞分析系统被HPRL鉴定。这些化合物的一个子集显示出以IRS2特有的方式刺激细胞生长的强大能力。一组选定的此类化合物将在啮齿动物和人类2-细胞中进行测试，并在小鼠身上进行体外和体内的铅优化研究。在这些研究成功完成后，应该会出现少量新的、铅优化的新分子实体，这些实体可能适合进入正式的临床前研究新药(IND)研究，用于治疗II型糖尿病患者。HPRL是一个功能齐全的化学和生物研究实验室，配备了用于现代分子和细胞生物学研究的设备，包括高通量筛选。通过SBIR第二阶段续签赠款机制提供的支持提供了利用HPRL的基础设施进行药物发现和设计前沿的新颖和创造性项目的机会。由于糖尿病是一种在世界范围内占很大比例的重大疾病，HPRL开发的药品和许可技术将拥有巨大的市场机会。

DESCRIPTION (provided by applicant): This is a Resubmission of an NIH Phase II SBIR Renewal Application directed towards developing and optimizing compounds that are capable of stimulating IRS2 foundation for the treatment of Type II diabetes. If successful, such compounds may also be useful for the treatment of a subset of patients with Type I diabetes as well. The overall goal of this proposal is to engage in lead optimization studies of new molecular entities already identified by HPRL scientists that activate the IRS2-branch of the insulin signal transduction cascade in mammalian cells. The NIH SBIR funding support will be used to focus research at Housey Pharmaceutical Research Laboratories (hereinafter "HPRL") to further develop for future commercialization initial discoveries made in the laboratory of Dr. Morris White at the Children's Hospital of Boston, Harvard Medical School, and investigators at the Joslin Diabetes Center. These discoveries have been licensed to HPRL for therapeutic applications. Compounds that activate the IRS2-branch of the insulin-mediated signal transduction cascade have been identified by HPRL as a result of a high throughput screen (HTS) using a target-protein specific cell-based assay system. A subset of these compounds exhibit substantial ability to stimulate cell growth in an IRS2- specific manner. A selected group of such compounds will undergo testing in rodent and human 2-cells together with both in-vitro and in-vivo lead optimization studies in mice. Following successful completion of these studies, a small number of novel, lead-optimized new molecular entities should emerge which may be suitable for advancement into formal preclinical investigational new drug (IND) studies for the treatment of patients with Type II diabetes. HPRL is a fully functional chemical and biological research laboratory that is equipped for modern molecular and cell biological studies, including high throughput screening. Support through the SBIR Phase II Renewal Grant mechanism provides the opportunity to utilize the infrastructure at HPRL for novel and creative projects at the cutting edge of drug discovery and design. Since diabetes is a major disease of substantial proportions world-wide, pharmaceutical products and licensable technologies developed by HPRL will have substantial market opportunities.