GIR Antagonists: Novel Feeding/Catabolism Molecules

描述（由申请人提供）：肥胖在美国已经成为流行病，每年造成超过520亿美元的直接医疗费用。有限的治疗选择和显著的副作用，目前使用的药物需要寻找新的和更好的药物靶点。P2D, Inc.开发了一种用于即时测试的非肽小分子拮抗剂，用于糖皮质激素诱导受体（GIR; GPCR 83）。GIR是一种神经肽y样受体，结合厌食肽PYY3-36和合成肽T-100。对先导化合物T-100（美国专利6013633和6235718 Bl）的初步研究表明，T-100可以显著减少不同喂养模式下大鼠的进食量。该1期SBIR将测试非肽小分子PD1-PD10，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结合和通过磷酸- creb对GIR介导的信号转导的拮抗作用。这些小分子GIR拮抗剂中最有效的将进行体内试验，目标是使T-100的饲料减少80%，并具有更好的中枢神经系统渗透和生物利用度。这些目标将在以下目标下实现：

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.