Novel Therapeutics for Cardiovascular Disease

心血管疾病的新疗法

• 批准号: 10440006
• 负责人: John C Burnett
• 金额: $ 71.56万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-12 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440006
• 关键词: ADME Study; Adrenal Glands; Aldosterone; Apoptosis; Arteries; Binding; Biological; Biological Availability; Biology; Blood Pressure; Brain natriuretic peptide; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Cessation of life; Chemosensitization; Chronic; Chronic Kidney Failure; Clinical; Coronary artery; Cyclic GMP; Development; Diuresis; Dose; Drug Kinetics; Drug Targeting; Endocrine Glands; Endothelial Cells; Engineering; Enzyme Inhibition; FDA approved; Fibrosis; Funding; Generations; Genes; Genetic; Goals; Guanosine Monophosphate; Health; Heart; Heart Atrium; Heart Hypertrophy; Heart failure; Homeostasis; Hormones; Human; Human Genetics; Hypertension; Hypertrophy; In Vitro; Inbred SHR Rats; Inflammation; Injectable; Kidney; Lead; Ligands; Measurement; Mediating; Metabolic; Molecular Bank; Molecular Target; Mus; Natriuresis; Oral; Particulate; Pathway interactions; Patients; Peptides; Periodicity; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Plasma; Production; Property; Receptor Activation; Renin-Angiotensin-Aldosterone System; Research; Resistant Hypertension; Risk; Second Messenger Systems; Signal Transduction; Stroke; System; Therapeutic; Time; United States National Institutes of Health; Vasodilation; Work; adverse outcome; atrial natriuretic factor receptor A; base; blood pressure reduction; clinical candidate; coronary event; design; drug discovery; efficacy study; genetic variant; high risk; high throughput screening; improved; in vivo; lead optimization; new therapeutic target; novel; novel drug class; novel therapeutics; positive allosteric modulator; premature; protective effect; prototype; receptor; repository; scaffold; small molecule; small molecule libraries; small molecule therapeutics; therapeutic target; urinary

PROJECT SUMMARY This application is to advance a paradigm-shift in particulate guanylyl cyclase A receptor (pGC-A) and 3’, 5’ cyclic guanosine monophosphate (cGMP) therapeutics with the development of a first-in-class small molecule targeting the pGC-A/cGMP pathway for cardiovascular disease (CVD). Our CV focus is on the unmet clinical need for novel therapeutic targets for hypertension (HTN), specifically resistant hypertension (RH), for which there are no approved drugs. The applicants have advanced the concept that the heart is an endocrine organ, which synthesizes ANP and BNP. Upon release, ANP and BNP bind to pGC-A , which is highly expressed in the heart, kidney and vasculature, and generates its second messenger, cGMP. The significance of the pGC-A/cGMP pathway in BP and CV homeostasis is supported by its biological actions which includes vasodilation, natriuresis, diuresis, suppression of hypertrophy, fibrosis, apoptosis and inflammation as well as inhibition of aldosterone. As RH patients are challenging to treat and have the highest risk adverse outcomes, the pleiotropic actions render pGC-A as an novel molecular target for CV therapeutics. To date, there are no small molecule pGC-A stimulators in existence. Through prior R01 funding, we discovered for the first time, pGC-A/cGMP small molecule scaffolds which function as positive allosteric modulators (PAMs) of which a potent derivative of our hit scaffold, MCUF-651, was engineered. Preliminary studies revealed that MCUF-651: 1) potentiates ANP/pGC-A mediated cGMP generation and reduces cardiomyocyte hypertrophy in vitro; 2) enhances ANP binding of pGC-A; 3) elevates cGMP and lowers BP in spontaneous hypertensive rats (SHRs) and 4) is orally bioavailable. Herein, we propose to advance our biological understanding of the cellular protective and BP lowering actions via small molecule pGC-A positive allosteric modulation utilizing the prototype, MCUF-651 and to pursue a drug discovery strategy to identify an optimized small molecule pGC-A PAM clinical candidate, building off MCUF-651. Aim 1: To define, in vitro, MCUF-651's cellular protective effects on pGC-A/cGMP mediated suppression of apoptosis and proliferation in human cardiorenal cells, inhibition of aldosterone in human adrenal cells, reduction in human coronary artery endothelial cell permeability and vasorelaxation in arteries. Aim 2: To establish, in vivo, the chronic cardiorenal protective, RAAS suppressing and BP lowering actions of orally administered MCUF-651 in SHRs. Aim 3: To perform lead optimization of MCUF-651 to improve potency and pharmacological properties, using iterative cycles of medicinal chemistry, selectivity profiling, functional potentiation and in vitro absorption, distribution, metabolism and excretion studies. Aim 4: To evaluate metabolic liabilities of MCUF-651 and subsequently, to advance prioritized optimized lead(s) to in vivo dose-dependent pharmacokinetic measurements and a chronic oral efficacy study in SHRs and to declare a first-in-class small molecule pGC-A stimulator for IND-enabling studies.

项目概要 该应用旨在推动颗粒鸟苷酸环化酶 A 受体 (pGC-A) 和 3'、5' 环状蛋白的范式转变 开发出一流的小分子靶向药物鸟苷单磷酸 (cGMP) 疗法 心血管疾病 (CVD) 的 pGC-A/cGMP 通路是我们未满足的临床需求。 高血压（HTN）的治疗目标，特别是难治性高血压（RH），目前尚无治疗目标 申请人具有心脏是内分泌器官的先进药物理念。 合成 ANP 和 BNP 释放后，ANP 和 BNP 与在心脏中高度表达的 pGC-A 结合， pGC-A/cGMP 的重要性。 BP 和 CV 稳态途径由其生物作用支持，包括血管舒张、尿钠排泄、 利尿、抑制肥大、纤维化、细胞凋亡和炎症以及抑制醛固酮。 RH 患者治疗具有挑战性，且不良后果风险最高，多效性作用使得 pGC-A 作为 CV 治疗的新型分子靶点 迄今为止，还没有小分子 pGC-A 刺激剂。 通过之前的 R01 资助，我们首次发现了 pGC-A/cGMP 小分子支架。 其功能为正变构调节剂 (PAM)，其是我们的命中支架的有效衍生物 MCUF-651， 初步研究表明 MCUF-651：1) 增强 ANP/pGC-A 介导的 cGMP。 体外产生并减少心肌细胞肥大；2) 增强 pGC-A 的 ANP 结合；3) 提高 cGMP 并降低自发性高血压大鼠 (SHR) 的血压，并且 4) 具有口服生物利用度。在此，我们建议： 我们对小分子 pGC-A 的细胞保护作用和降压作用的生物学理解 利用原型 MCUF-651 进行正变构调节，并采取药物发现策略来识别 优化的小分子 pGC-A PAM 临床候选药物，以 MCUF-651 为基础，目标 1：在体外定义， MCUF-651 对 pGC-A/cGMP 介导的细胞凋亡和增殖抑制的细胞保护作用 人心脏细胞，抑制人肾上腺细胞中的醛固酮，减少人冠状动脉 目标 2：在体内建立慢性心肾功能。 口服 MCUF-651 在 SHR 中的保护、RAAS 抑制和降压作用 目标 3： 使用迭代循环对 MCUF-651 进行先导化合物优化，以提高效力和药理特性 药物化学、选择性分析、功能增强和体外吸收、分布、代谢 目标 4：评估 MCUF-651 的代谢负债，并随后推进。 优先优化体内剂量依赖性药代动力学测量和长期口服疗效的先导化合物 SHR 的研究，并宣布用于 IND 研究的一流小分子 pGC-A 刺激剂。