Allosteric modulators of the glucagon-like peptide-1 receptor

描述（由申请人提供）：最近2型糖尿病治疗的创新集中在肠道来源的肠促胰岛素激素上，这种激素对胰岛素分泌、饱腹感和体重有明显的影响。其中一种激素，胰高血糖素样肽-1 (GLP-1)，餐后从肠道释放，并通过其家族G蛋白偶联受体（GPCR）增强胰腺β细胞葡萄糖依赖性胰岛素分泌（以及许多其他活动）。一般来说，用小分子“药物化”gpcr是非常成功的。然而，GLP-1受体（GLP1R）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（通过与其他地方结合或自身诱导活性的小分子增强或抑制正构位点配体产生的活性）是靶向GLP1R的一种有吸引力的模式。我们已经完成了一项高通量筛选和初步的结构活性工作，其中鉴定了约200种具有独特药理活性模式的化合物，包括GLP1R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模拟文库合成方法，优化先导化合物的性质，使其能够在体内用作分析GLP-1R调制独特模式在健康和疾病中的作用的工具。我们将开发外周受限以及cns渗透探针，以解决体内突出的生物学问题。文库将在一套体外药理学试验中进行测试，以评估效力、疗效、选择性，这些数据将用于进一步的药物化学和DMPK工作的分类。那些具有化学和药理价值的化合物将被推进到体外和体内药物代谢和药代动力学（DMPK）研究中，使用现代方法来鉴定、优化和配制具有良好药物样特性（+/- CNS外显率）的化合物，用于体内研究。为了测试外周限制性或中心渗透性GLP1R阳性pam的生理意义，我们将利用最先进的体内葡萄糖稳态方法的变化，包括在存在和不存在不同浓度的肽GLP1R激动剂的情况下葡萄糖和胰岛素夹紧。我们还将测试影响，特别是CNS渗透化合物，对与CNS GLP1R信号相关的行为，如喂养和神经保护。虽然基于GLP-1的治疗方法在糖尿病和体重控制方面有明显的疗效，但也存在显著的缺陷。我们假设通过PAM“微调”GLP1R信号提供了优化糖尿病、肥胖和其他疾病治疗结果的潜力。这种方法可以利用天然GLP-1分泌，也可以与其他GLP-1靶向治疗相结合。拟议的研究将产生工具，并初步证明这种方法可能提供优势的概念。

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.