GIR Antagonists: Novel Feeding/Catabolism Molecules

GIR 拮抗剂：新型喂养/分解代谢分子

• 批准号: 7056403
• 负责人: SOMASUNDAR PRASAD GABBITA
• 金额: $ 17.44万
• 依托单位: P2D, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056403
• 关键词: anorexic agent; bioenergetics; biological signal transduction; body weight; cAMP response element binding protein; calorimetry; cell line; cell surface receptors; drug design /synthesis /production; drug screening /evaluation; eating; intraperitoneal injections; laboratory rat; obesity; pharmacokinetics; receptor binding; small molecule

DESCRIPTION (provided by applicant): Obesity has risen to epidemic proportions in the United States, contributing to over 52 billion USD per year in direct medical costs. Limited treatment options and significant side effects of currently used Pharmaceuticals necessitate the search for new and better pharmaceutical targets. P2D, Inc. has developed for immediate testing, non-peptide small molecule antagonists of a novel feeding target, glucocorticoid-induced receptor (GIR; GPCR 83). GIR is a neuropeptide Y-like receptor that binds anorectic peptide PYY3-36 as well as synthetic peptide T-100. Preliminary studies of the lead compound, T-100 (US patents 6013633 & 6235718 Bl), demonstrate that T-100 significantly attenuates food intake in rats using different feeding paradigms. This Phase 1 SBIR will test non-peptide small molecules, PD1-PD10, derived from T-100 structure-activity assessment of the GIR pharmacophore. First, compounds will be tested for GIR binding and antagonism of GIR-mediated signal transduction via phospho-CREB. The most potent of these small molecule GIR antagonists will then undergo in vivo testing with a goal to achieve the 80% reduction of feeding seen with T-100, with better CNS penetration and bioavailability properties. These goals will be achieved under the following Aims, Specific Aim 1: Compounds PD1 through PD10 will be tested for biological activity in vitro using a cell line (GIRD7) that expresses the novel NPY-like receptor GIR. Compounds PD1 to PD10 will be tested for binding to GIR expressed in GIRD7 cells by competition assays and for antagonism of pCREB- induced luciferase activation mediated by GIR in GIRD7 cells. Efficacy of non-peptide compounds for binding and functional antagonism of GIR will be compared to that observed for peptide antagonist T-100. Specific Aim 2: In vivo testing of drug candidates in animal models of feeding behavior and energy expenditure. The three most potent candidates (as determined by Specific Aim 1) will be tested in rats for effects on food intake, energy expenditure, conditioned taste aversion. CNS penetration and dose- response behavior will be evaluated in two routes of administration, intracerebroventricular (i.c.v). vs. intraperitoneal (i.p.) T-100 will be employed as a positive control.

描述（由申请人提供）：肥胖在美国已成为流行病，每年造成的直接医疗费用超过 520 亿美元。目前使用的药物治疗选择有限且副作用显着，因此需要寻找新的、更好的药物靶点。 P2D, Inc. 开发了用于立即测试的新型喂养靶标糖皮质激素诱导受体（GIR；GPCR 83）的非肽小分子拮抗剂。 GIR 是一种神经肽 Y 样受体，可结合厌食肽 PYY3-36 以及合成肽 T-100。对先导化合物 T-100（美国专利 6013633 和 6235718 B1）的初步研究表明，T-100 显着减少使用不同喂养方式的大鼠的食物摄入量。该 1 期 SBIR 将测试非肽小分子 PD1-PD10，其源自 GIR 药效团的 T-100 结构活性评估。首先，将测试化合物的 GIR 结合以及通过磷酸-CREB ​​拮抗 GIR 介导的信号转导。这些小分子 GIR 拮抗剂中最有效的药物将接受体内测试，目标是使 T-100 的进食量减少 80%，并具有更好的 CNS 渗透性和生物利用度。这些目标将在以下目标下实现， 具体目标 1：将使用表达新型 NPY 样受体 GIR 的细胞系 (GIRD7) 在体外测试化合物 PD1 至 PD10 的生物活性。将通过竞争测定测试化合物PD1至PD10与GIRD7细胞中表达的GIR的结合以及对GIRD7细胞中GIR介导的pCREB诱导的荧光素酶活化的拮抗作用。将非肽化合物对 GIR 的结合和功能性拮抗作用的功效与肽拮抗剂 T-100 观察到的功效进行比较。 具体目标 2：在动物模型的摄食行为和能量消耗中对候选药物进行体内测试。将在大鼠中测试三种最有效的候选药物（根据具体目标 1 确定）对食物摄入、能量消耗、条件性味觉厌恶的影响。中枢神经系统渗透和剂量反应行为将通过两种给药途径进行评估：脑室内（i.c.v）。与腹膜内 (i.p.) T-100 相比将用作阳性对照。