Allosteric modulators of the glucagon-like peptide-1 receptor

描述（由申请人提供）：2型糖尿病治疗的最新创新集中在对胰岛素分泌、饱腹感和体重有明显影响的肠促胰岛素激素上。一种这样的激素，胰高血糖素样肽-1（GLP-1），餐后从肠释放，并通过其家族B G蛋白偶联受体（GPCR）增强胰腺β细胞的葡萄糖依赖性胰岛素分泌（在许多其他活性中）。GPCR通常被小分子高度成功地“麻醉”。然而，GLP-1受体（GLP 1 R）可能由于其大而复杂的正构结合位点而未能成功靶向小分子。因此，变构调节（通过结合其他地方或自身诱导活性的小分子增强或抑制正构位点中配体产生的活性）是一种有吸引力的靶向GLP 1 R的模式。我们已经完成了高通量筛选和初步的结构-活性工作，其中已经鉴定了约200种具有独特药理活性模式的化合物，包括GLP 1 R的正变构调节（PAM）和变构激动剂。在这里，我们将采用多维迭代类似物库合成方法，优化先导化合物的特性，使其能够在体内用作剖析GLP-1 R调节的独特模式在健康和疾病中的作用的工具。我们将开发外周限制以及CNS渗透探针，以解决体内突出的生物学问题。将在一套体外药理学试验中对文库进行检测，以评估效价、疗效、选择性，这些数据将用于进一步药物化学和DMPK工作的分类。具有化学和药理学优点的那些化合物将被推进到体外和体内药物代谢和药代动力学（DMPK）研究，使用当代方法来鉴定、优化和配制具有有利的药物样性质（+/- CNS代谢率）的化合物以用于体内研究。为了测试外周限制性或中枢渗透性阳性GLP 1 R PAM的生理学意义，我们将利用最先进的体内葡萄糖稳态方法的变体，包括在存在和不存在不同浓度的肽GLP 1 R激动剂的情况下进行葡萄糖和胰岛素钳夹。我们还将测试效果，特别是中枢神经系统渗透剂化合物，对与中枢神经系统GLP 1 R信号传导相关的行为，如进食和神经保护。虽然基于GLP-1的治疗剂在糖尿病和体重控制中具有明确的功效，但存在显著的缺点。我们假设，通过PAM“微调”GLP 1 R信号提供了优化糖尿病，肥胖症和其他疾病的治疗结果的潜力。这种方法可以利用天然GLP-1分泌，或者可以与其他GLP-1靶向治疗剂联合治疗。拟议的研究将产生工具，并初步证明这种方法可能提供的优势。

DESCRIPTION (provided by applicant): Recent innovations in type 2 diabetes therapeutics have focused on gut-derived incretin hormones that have distinct effects on insulin secretion, satiety, and body weight. One such hormone, glucagon-like peptide-1 (GLP-1), is released post-prandially from the intestine and potentiates glucose-dependent insulin secretion from pancreatic beta cells (among many other activities) via its family B G protein-coupled receptor (GPCR). GPCRs in general been highly successfully "drugged" with small molecules. The GLP-1 receptor (GLP1R), however, has eluded successful small molecule targeting likely because its large, complex orthosteric binding sites. Allosteric modulation (potentiation or suppression of activity generated by ligand in the orthosteric site by a small molecule that binds elsewhere or induces activity on its own), was therefore, an attractive mode of targeting the GLP1R. We have completed a high-throughput screen and initial structure-activity work in which ~200 compounds with unique modes of pharmacological activity, including positive allosteric modulation (PAM) and allosteric agonists of the GLP1R have been identified. Here we will employ a multi-dimensional iterative analog library synthesis approach, to optimize lead compound(s) for properties enabling in vivo use as a tool to dissect the role of unique modes of GLP-1R modulation in health and disease. We will develop both peripherally restricted as well as CNS-penetrant probes in order to address outstanding biological questions in vivo. Libraries will be tested in a suite of in vitro pharmacology assays to assess potency, efficacy, selectivity and these data will be utilized to triage for further medicinal chemistry and DMPK efforts. Those compounds possessing chemical and pharmacological merit will be advanced to in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies using contemporary methodology to identify, optimize, and formulate compounds with favorable drug-like properties (+/- CNS penetrance) for use in in vivo studies. In order to test the physiological significance of either peripherally restricted or centrally penetrant positive GLP1R PAMs we will utilize variations of state-of-the-art in vivo glucose homeostasis methods involving glucose and insulin clamping in the presence and absence of varying concentrations of peptide GLP1R agonist. We will also test effects, particularly of CNS penetrant compounds, on behaviors related to CNS GLP1R signaling such as feeding and neuroprotection. While GLP-1 based therapeutics have clear efficacy in diabetes and weight control, significant liabilities exist. We hypothesize that "fine-tuning" GLP1R signaling via PAM offers the potential to optimize therapeutic outcomes in diabetes, obesity, and other disorders. This approach may capitalize on native GLP-1 secretion, or may be coupled to combination therapy with other GLP-1 targeted therapeutics. The proposed studies will generate the tools, and initial proof-of-concept that such an approach may offer advantages.