Allosteric modulators of the glucagon-like peptide-1 receptor

胰高血糖素样肽-1 受体的变构调节剂

• 批准号: 8996184
• 负责人: CRAIG LINDSLEY
• 金额: $ 16.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996184
• 关键词: Address; Agonist; Allosteric Regulation; Amino Acids; Behavior; Behavioral Assay; Binding; Binding Sites; Biological; Biological Assay; Blood Glucose; Body Weight; Brain; Cell Line; Cells; Chemicals; Chemistry; Chemosensitization; Combined Modality Therapy; Complex; Coupled; Cyclic AMP; Data; Development; Diabetes Mellitus; Disease; Drug Kinetics; Effectiveness; Ensure; Family; G-Protein-Coupled Receptors; GCG gene; Glucagon Receptor; Glucose; Glucose tolerance test; Goals; Health; Hormones; Human; In Vitro; Intestines; Islets of Langerhans; Lead; Learning; Libraries; Ligands; Liver; Mediating; Melanocortin 4 Receptor; Memory; Metabolic; Methodology; Methods; Modeling; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Penetrance; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Pre-Clinical Model; Production; Property; Receptor Signaling; Regulation; Rodent; Role; Satiation; Series; Signal Transduction; Site; Stress; Structure; Structure of beta Cell of islet; Structure-Activity Relationship; Testing; Therapeutic; Tissues; Triage; Variant; Weight maintenance regimen; Work; analog; base; blood glucose regulation; counterscreen; design; diabetes control; drug metabolism; exenatide; feeding; glucagon-like peptide; glucagon-like peptide 1; glucose and insulin clamps; glucose metabolism; high throughput screening; in vivo; incretin hormone; inhibitor/antagonist; innovation; insulin secretion; liraglutide; neuroprotection; novel; pharmacodynamic model; positive allosteric modulator; receptor; release of sequestered calcium ion into cytoplasm; screening; small molecule; targeted treatment; therapy outcome; tool

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.

描述（由申请人提供）：2 型糖尿病治疗的最新创新集中在肠道来源的肠促胰岛素激素上，该激素对胰岛素分泌、饱腹感和体重具有明显的影响。其中一种激素，胰高血糖素样肽-1 (GLP-1)，在餐后从肠道释放，并通过其家族 BG 蛋白偶联受体增强胰腺 β 细胞的葡萄糖依赖性胰岛素分泌（以及许多其他活性）。 GPCR）。一般来说，GPCR 都非常成功地被小分子“麻醉”。然而，GLP-1 受体 (GLP1R) 未能成功实现小分子靶向，可能是因为其大而复杂的正位结合位点。因此，变构调节（通过与别处结合或自身诱导活性的小分子增强或抑制配体在正位点产生的活性）是一种针对 GLP1R 的有吸引力的模式。我们已经完成了高通量筛选和初步结构活性工作，其中鉴定出约 200 种具有独特药理活性模式的化合物，包括正变构调节 (PAM) 和 GLP1R 的变构激动剂。在这里，我们将采用多维迭代模拟库合成方法，优化先导化合物的特性，使其能够在体内用作剖析 GLP-1R 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性探针和中枢神经系统渗透探针，以解决体内突出的生物学问题。文库将在一系列体外药理学测定中进行测试，以评估效力、功效和选择性，这些数据将用于对进一步的药物化学和 DMPK 工作进行分类。这些具有化学和药理学优点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，使用当代方法来识别、优化和配制具有有利的药物特性（+/- CNS 外显率）的化合物以供使用在体内研究中。为了测试外周限制性或中枢渗透性阳性 GLP1R PAM 的生理意义，我们将利用各种最先进的体内葡萄糖稳态方法，包括在存在和不存在不同浓度的肽 GLP1R 的情况下进行葡萄糖和胰岛素钳制激动剂。我们还将测试对 CNS GLP1R 信号传导相关行为（例如进食和神经保护）的影响，特别是 CNS 渗透化合物。虽然基于 GLP-1 的疗法在糖尿病和体重控制方面具有明显的功效，但也存在重大缺陷。我们假设通过 PAM“微调”GLP1R 信号传导有可能优化糖尿病、肥胖症和其他疾病的治疗结果。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具有的优势。