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; 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）：肥胖已与美国的流行比例增加，每年的直接医疗费用每年超过520亿美元。有限的治疗选择和当前使用药品的重大副作用需要寻找新的，更好的药物靶标。 P2D，Inc。已开发用于新型喂养靶标，糖皮质激素诱导的受体（GIR； GPCR 83）的即时测试，非肽小分子拮抗剂。 GIR是一种神经肽Y样受体，它结合了厌氧肽PYY3-36以及合成肽T-100。铅化合物T-100的初步研究（美国专利6013633＆6235718 BL）表明，使用不同的喂养范式，T-100显着减轻大鼠的食物摄入。该第1阶段SBIR将测试非肽小分子PD1-PD10，该分子源自GIR药理的T-100结构活性评估。首先，将测试化合物通过磷酸核BREB的GIR介导的信号转导的GIR结合和拮抗作用。这些小分子GIR拮抗剂中最有效的人将进行体内测试，目标是实现T-100所看到的80％降低，具有更好的CNS穿透性和生物利用度。这些目标将在以下目标下实现 具体目标1：使用表达新型NPY样受体GIR的细胞系（Gird7），将在体外测试化合物PD1至PD10的化合物。通过竞争测定法和PCREB诱导的荧光素酶激活的拮抗作用，将测试化合物PD1至PD10的与GIRD7细胞中GIR的结合。非肽化合物对GIR的结合和功能拮抗作用的功效将与观察到的肽拮抗剂T-100进行比较。 特定目的2：在动物模型的饲喂行为和能量消耗的动物模型中对候选药物的体内测试。将在大鼠中测试三个最有效的候选者（由特定目标1所确定），以对食物摄入，能量消耗，条件味觉厌恶的影响。中枢神经系统渗透和剂量反应行为将在两种给药途径中评估，室内室内（I.C.V）。腹膜内（i.p.）T-100将被用作阳性对照。