Negative allosteric modulators for bradykinin B1 receptors

缓激肽 B1 受体的负变构调节剂

基本信息

批准号：
10680762
负责人：
KELLY ANN BERG
金额：
$ 23.25万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-21 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680762
关键词：
Affinity Agonist Asthma Biological Models Bradykinin Cells Chemicals Clinical Trials Core Facility Data Diabetic Retinopathy Disease Drug Targeting Edema Evaluation Exposure to Failure Future Goals Health Human Human Activities Inflammation Inflammation Mediators Kallidin Libraries Ligands Malignant Neoplasms Neuropathy Normal tissue morphology Obesity Pain Pathologic Pathology Pharmaceutical Preparations Pharmacotherapy Phase Physiological Pre-Clinical Model Property Reporting Rodent Role Safety Specificity Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Therapeutic Uses Tissues Toxic effect Vascular Diseases Work antagonist chronic pain drug action drug development drug-like compound effective therapy efficacy testing experimental analysis high risk high throughput screening in vivo innovation lung microvascular endothelial cells novel pharmacologic receptor receptor expression receptor function screening small molecule small molecule libraries species difference therapeutic development therapeutically effective

项目摘要

Bradykinin (BK) B1 receptor (BKB1R) activity is involved in a wide range of pathological conditions including edema, inflammation, asthma, chronic pain, vasculopathy, neuropathy, obesity, diabetic retinopathy and cancer. Antagonists of these receptors would be expected to be of great therapeutic utility, however, although several BKB1R antagonists have entered clinical trials, none have emerged successfully from Phase II. BKB1Rs are generally not expressed in most tissues unless exposed to inflammatory mediators and when expressed, have a high level of constitutive (agonist-independent) receptor activity. Although the reasons for the failure of BKB1R antagonists in clinical trials have not been reported, it is likely that the high level of constitutive activity of the BKB1R, which is not reduced by standard antagonists, is responsible for efficacy failures. Reduction of constitutive receptor activity requires an orthosteric ligand with inverse agonist activity or a negative allosteric regulator. Unfortunately, the only known orthosteric inverse agonists for the BKB1R are very weak and there are no allosteric regulators that reduce constitutive activity. The premise underlying this project is that reduction of constitutive BKB1R activity is an important component of a therapeutically effective antagonist. The goal of this project is to identify novel compounds that reduce BKB1R function by both antagonizing the endogenous agonist (des-Arg10-kallidin) and reducing constitutive BKB1R activity. This effect can be obtained with an orthosteric inverse agonist or a negative allosteric modulator (NAM). In Aim 1a, we propose to screen a library of ~170,000 small molecules to identify compounds that reduce agonist-activated and constitutive activity of the human BKB1Rs expressed in HEK cells. In Aim 1b, we will screen hits from Aim 1a to eliminate compounds that have non-specific effects or that alter BKB2R activity. In Aim 1c, compounds from Aim 1b will be rigorously tested pharmacologically (e.g. Schild analysis experiments) to identify allosteric versus orthosteric mechanisms of action. As NAMs have several advantages over orthosteric ligands, including specificity, safety and the ability to fine-tune receptor function along with reducing constitutive receptor activity, we will prioritize NAMs over orthosteric inverse agonists. Finally, in Aim 1d we will confirm that the BKB1 NAMs and inverse agonists function as expected when BKB1Rs are naturally expressed using human lung microvascular endothelial cells. This work will provide the preliminary data and candidate molecules needed to move forward to IND-enabling studies. Although this project is high risk, the identification of first-in-class negative allosteric regulators that reduce constitutive activity of human BKB1Rs is highly desirable.

缓激肽 (BK) B1 受体 (BKB1R) 活性与多种病理状况有关，包括水肿、炎症、哮喘、慢性疼痛、血管病变、神经病变、肥胖、糖尿病视网膜病变和癌症。然而，这些受体的拮抗剂有望具有巨大的治疗效用，尽管有几种 BKB1R 拮抗剂已进入临床试验，但尚未成功完成 II 期试验。 BKB1R 是通常在大多数组织中不表达，除非暴露于炎症介质，并且当表达时，高水平的组成型（非激动剂依赖性）受体活性。虽然BKB1R失败的原因临床试验中的拮抗剂尚未见报道，很可能是该拮抗剂的高水平组成活性 BKB1R 不会被标准拮抗剂降低，这是导致疗效失败的原因。减少组成型受体活性需要具有反向激动剂活性或负变构的正构配体调节器。不幸的是，唯一已知的 BKB1R 正向反向激动剂非常弱，并且有没有减少组成活性的变构调节剂。该项目的前提是减少组成型 BKB1R 活性是治疗有效的拮抗剂的重要组成部分。此举的目标该项目的目的是鉴定通过拮抗 BKB1R 功能来降低 BKB1R 功能的新型化合物内源性激动剂（des-Arg10-激肽）并降低组成型 BKB1R 活性。这个效果可以通过正构反激动剂或负变构调节剂（NAM）获得。在目标 1a 中，我们建议筛选约 170,000 个小分子的库，以鉴定可减少激动剂激活和 HEK 细胞中表达的人类 BKB1R 的组成型活性。在 Aim 1b 中，我们将筛选来自 Aim 的点击 1a 消除具有非特异性作用或改变 BKB2R 活性的化合物。在目标 1c 中，化合物来自 Aim 1b 的产品将经过严格的药理学测试（例如 Schild 分析实验）以鉴定变构与正位作用机制。由于 NAM 比正构配体具有多种优势，包括特异性、安全性和微调受体功能以及降低受体活性的能力，我们将优先考虑 NAM 而非正构反激动剂。最后，在目标 1d 中，我们将确认 BKB1 NAM 当 BKB1R 使用人肺自然表达时，反向激动剂按预期发挥作用微血管内皮细胞。这项工作将提供所需的初步数据和候选分子推进 IND 支持研究。虽然该项目风险较高，但一流的鉴定降低人类 BKB1R 组成活性的负变构调节剂是非常需要的。