NOVEL NON-PEPTIDE ANTAGONIST OF THE MCH RECEPTOR

描述：（从申请人的描述扫描）的患病率 肥胖症在美国人口的各个阶层中急剧上升， 过去二十年。最近的研究表明， 黑色素浓集激素（MCH）在控制摄食行为和机体中的作用 重量.例如，在大鼠中直接中枢施用MCH肽 增加进食。此外，缺乏MCH基因的小鼠吃得明显少 体重减少了25- 30%。这些 观察结果为MCH拮抗剂的开发提供了令人信服的基础 作为治疗肥胖和糖尿病的新药。在初步实验中， 我们已经鉴定了许多对该化合物具有低微摩尔亲和力的化合物， MCH受体，包括亲和力低于微摩尔的化合物 范围在第一阶段，我们提出了一种高通量并行合成方法， 生成小分子文库，以开发具有高 亲和力我们还将研究这些化合物的功能效应 并确定它们对MCH受体的特异性， 受体。最后，我们将在大鼠MCH诱导的 喂养模型，以评价它们在体内阻断MCH的能力。具体目标 第一阶段提出的设计旨在产生有效的小分子MCH受体 拮抗剂，以及必要的数据，以支持发展， 将这些拮抗剂转化为II期有效的临床候选物。 拟定商业应用： 这项研究如果成功，将产生黑色素的小分子拮抗剂- 集中激素受体，选择性地抑制进食反应。口头 小分子MCH受体拮抗剂的活性形式将提供一种新的 适应症如肥胖症和糖尿病的治疗策略。

DESCRIPTION: (Scanned from the applicant's description) The prevalence of obesity has risen dramatically among all segments of the U.S. population in the last two decades. Recent studies have established a role for melanin-concentrating hormone (MCH) in the control of feeding behavior and body weight. For example, direct central administration of the MCH peptide in rats increases feeding. Also, mice that lack the MCH gene eat significantly less than control mice and have a 25-30 percent reduction in body weight. These observations provide a compelling basis for the development of MCH antagonists as novel drug treatments for obesity and diabetes. In preliminary experiments, we have identified a number of compounds with low micromolar affinity for the MCH receptor, including compounds that have affinities below the micromolar range. In Phase I, we propose a high throughput parallel synthesis approach to generate small molecule libraries in order to develop multiple leads with high affinity. We will also investigate the functional effects of these compounds and determine their specificity for the MCH receptor compared to related receptors. Finally, we will examine selected compounds in a rat MCH-induced feeding model for their ability to block MCH in vivo. The specific aims proposed in Phase I are designed to generate potent small molecule MCH receptor antagonists, together with the data necessary to support the development of these antagonists into valid clinical candidates in Phase II. PROPOSED COMMERCIAL APPLICATION: This research, if successful, will result in small molecule antagonists of the melanin- concentrating hormone receptor that selectively inhibits the feeding response. Orally active forms of a small molecule MCH receptor antagonist would provide a novel therapeutic strategy for indications such as obesity and diabetes.