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(申请人提供)：肥胖症在美国已经上升到流行的比例，每年造成超过520亿美元的直接医疗费用。目前使用的药物治疗选择有限，副作用严重，因此有必要寻找新的、更好的药物靶点。P2D，Inc.已开发出用于立即测试的新型摄食靶标--糖皮质激素诱导受体(GIR；GPCR83)的非肽小分子拮抗剂。GIR是一种神经肽Y样受体，与厌食肽PYY3-36和合成肽T-100结合。对先导化合物T-100的初步研究(美国专利6013633&6235718 B1)表明，T-100显著减少了使用不同喂养模式的大鼠的食物摄入量。这一阶段的SBIR将测试非肽小分子PD1-PD10，它来自于GIR药效团的T-100结构-活性评估。首先，将测试化合物的GIR结合和拮抗通过磷酸化CREB介导的GIR信号转导。然后，这些最有效的小分子GIR拮抗剂将接受体内测试，目标是实现与T-100相同的80%的喂食量减少，并具有更好的中枢神经系统渗透和生物利用度特性。这些目标将在以下目标下实现， 具体目标1：将使用表达新的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。化合物PD1至PD10将通过竞争试验检测与GIRD7细胞中表达的GIR的结合，以及对GIRD7细胞中GIR介导的pCREB诱导的荧光素酶激活的拮抗作用。非肽化合物对GIR的结合和功能拮抗作用的有效性将与多肽拮抗剂T-100的观察结果进行比较。 具体目标2：在动物模型中测试候选药物的摄食行为和能量消耗。三个最有效的候选者(由特定目标1确定)将在老鼠身上测试对食物摄入量、能量消耗和条件味觉厌恶的影响。中枢神经系统的渗透性和剂量-反应行为将通过两种给药途径进行评估，即脑室内给药(i.c.v)。与腹膜腔内(I.P.)采用T-100作为阳性对照。