A New Drug for Depression

描述（由申请人提供）： 长期目标：Serenix Pharmaceuticals（SP）将开发用于 治疗CNS病症。 策略：SP从Eli获得一系列加压素受体拮抗剂 礼来公司，并通过操纵这些分子， 不同的结构区。这些拮抗剂的一个子集（铅系列）表现出 与抑郁症相关的血管加压素受体亚型的合理亲和力 和压力相关的情感障碍铅系列需要改进， 优化亲和力（小于5.0 nM）和早期测试，以证明 生物活性平台分子具有四个基本结构区; 其中两项将是拟议研究的重点。第一阶段的目标是 (i)利用经典化学和组合化学来修饰 LEAD SERIES生成CA。200种化合物，（ii）筛选这些目标 受体亲和力，并集中在那些与Kd小于5 nM，和（iii）测试 体外生物活性的高亲和力化合物。调查结果， 结合与亲和力，结构多样性， 结构吸引力和QSAR模型，将确定有前途的化合物 用于II期口服吸收、稳定性、代谢、毒性试验， 和功效。 拟定商业应用：SP将专注于开发一种治疗抑郁症和与压力有关的情感障碍的新药。1999年，NIMH报告说，抑郁症影响了美国超过19，000，000名成年人，使其成为最常见的严重CNS疾病。拟议的药物代表了一种新的药理学方法，不同于目前用于这些疾病的三环类药物，SSRI和NRI。因此，它可以占据重要的市场份额。

DESCRIPTION (provided by applicant): Long Term Goals: Serenix Pharmaceuticals (SP) will develop drugs for the treatment of CNS disorders. Strategy: SP acquired a series of vasopressin receptor antagonists from Eli Lilly and Company and has refined these molecules through manipulations of various structural zones. A subset of these antagonists (LEAD SERIES) exhibit reasonable affinity for the vasopressin receptor subtype involved in depression and stress-related affective disorders. The LEAD SERIES requires refinement to optimize affinity (less than 5 .0 nM) and early stage testing to demonstrate biological activity. The platform molecule has four essential structural zones; two of these will be the focus of the proposed research. Phase I objectives are (i) utilize classical and combinatorial chemistry to modify structural zones on the LEAD SERIES to generate ca. 200 compounds, (ii) screen these for target receptor affinity and focus on those with Kds less than 5 nM, and (iii) test the high affinity compounds for in vitro biological activity. The findings, combined with considerations related to affinity, structural diversity, structural attractiveness, and QSAR models, will identify promising compounds for testing in Phase II for oral absorption, stability, metabolism, toxicity, and efficacy. PROPOSED COMMERCIAL APPLICATION: SP will focus on the development of a novel drug for the treatment of depression and stress-related affective disorders. In 1999, the NIMH reported that depression affects over 19,000,000 adults in the United States, making it the most common serious CNS disease. The proposed drug represents a novel pharmacological approach that differs from the tricyclics, SSRIs, and NRIs currently used for these disorders. It therefore may capture significant market share.