GIR Antagonists: Novel Feeding/Catabolism Molecules

描述（由申请人提供）：肥胖在美国已经上升到流行病的比例，每年直接医疗费用超过520亿美元。有限的治疗选择和目前使用的药物的显着副作用需要寻找新的和更好的药物靶点。P2 D公司已经开发了一种新的摄食靶点糖皮质激素诱导受体（GIR; GPCR 83）的非肽小分子拮抗剂，用于立即测试。GIR是神经肽Y样受体，其结合厌食肽PYY 3 -36以及合成肽T-100。先导化合物T-100（美国专利6013633和6235718 B1）的初步研究表明，T-100在使用不同喂养模式的大鼠中显著减弱食物摄入。该1期SBIR将检测非肽小分子PD 1-PD 10，其来源于GIR药效团的T-100结构-活性评估。首先，将测试化合物的GIR结合和经由磷酸-CREB的GIR介导的信号转导的拮抗作用。然后，这些小分子GIR拮抗剂中最有效的将进行体内测试，目标是实现T-100观察到的摄食减少80%，具有更好的CNS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：将使用表达新型NPY样受体GIR的细胞系（GIRD 7）测试化合物PD 1至PD 10的体外生物活性。将通过竞争测定测试化合物PD 1至PD 10与GIRD 7细胞中表达的GIR的结合，并测试化合物PD 1至PD 10对GIRD 7细胞中由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对肽拮抗剂T-100观察到的功效进行比较。 具体目标2：在摄食行为和能量消耗的动物模型中进行候选药物的体内测试。将在大鼠中测试三种最有效的候选物（如通过特定目标1确定的）对食物摄入、能量消耗、条件性味觉厌恶的影响。将在两种给药途径（脑室内（i.c.v））中评价CNS渗透和剂量反应行为。vs.腹膜内（i. p.）T-100将用作阳性对照。

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.