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Novel oral therapeutics for multiple sclerosis

多发性硬化症的新型口服疗法

基本信息

批准号：
7022307
负责人：
SUBRAMANIAM SRIRAM
金额：
$ 14.49万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2007-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Over the last few years we have (in collaboration with Bexel Pharmaceuticals, Hayward CA) developed novel orally bio-available water-soluble drugs with potent in vitro and in vivo anti-inflammatory properties. These compounds were initially generated as derivatives of thiazolidinediones (TZD's) which are known to bind and activate the nuclear transcription factor, PPAR gamma (peroxisome proliferator-activated receptor). TZD compounds which were discovered more than 20 years ago, and was tested for its lipid lowering effects were subsequently found to be effective for the treatment of Type II diabetes. Unlike the parent TZD compounds, our novel compounds do not appear to act as ligands for PPAR gamma but instead demonstrate potent anti-inflammatory properties in vitro, without inducing any metabolic effects of TZD's. We believe, that these novel non-PPAR gamma binding TZD analogues form a new class of anti-inflammatory agents with high potential in the treatment of inflammatory disorders, including those that are autoimmune. In view of our expertise in CNS inflammatory demyelinating disorders, our proposal seeks to address the efficacy of N-PPAR gamma-TZD's in autoimmune model disease systems that have been shown to be relevant to human MS, such as experimental allergic encephalitis. While the focus of the present proposal seeks to address the relevant pre-clinical studies pertaining to inflammatory diseases of the CNS, we believe that the ultimate use of these drugs may not be limited to this disease alone but are likely to be extended to other autoimmune diseases.

描述（由申请人提供）：在过去的几年中，我们（与海沃德CA的Bexel制药公司合作）开发了具有有效体外和体内抗炎特性的新型口服生物可溶水溶性药物。这些化合物最初是作为噻唑烷二酮（TZD）的衍生物产生的，已知TZD可以结合并激活核转录因子PPAR γ（过氧化物酶体增殖物激活受体）。早在20多年前，人们就发现了TZD化合物，并对其降脂作用进行了测试，随后发现它对治疗II型糖尿病有效。与母体TZD化合物不同，我们的新化合物似乎不作为PPAR γ的配体，而是在体外表现出有效的抗炎特性，而不会诱导TZD的任何代谢作用。我们相信，这些新的非ppar γ结合TZD类似物形成了一类新的抗炎药，在治疗炎症性疾病（包括自身免疫性疾病）方面具有很高的潜力。鉴于我们在中枢神经系统炎症性脱髓鞘疾病方面的专业知识，我们的提案旨在解决N-PPAR γ - tzd 's在已被证明与人类MS相关的自身免疫性模型疾病系统中的功效，如实验性过敏性脑炎。虽然本提案的重点是寻求解决与中枢神经系统炎症性疾病相关的临床前研究，但我们相信这些药物的最终应用可能不仅限于这种疾病，而且可能扩展到其他自身免疫性疾病。