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.

项目总结 这一应用是为了推进颗粒鸟苷酸环化酶A受体(PGC-A)和3‘，5’环的范式转变 鸟苷一磷酸(CGMP)疗法与一流小分子靶向的开发 PGC-A/cGMP途径在心血管疾病中的作用我们的简历关注的是未得到满足的临床需求 高血压(HTN)的治疗目标，特别是顽固性高血压(RH)，目前还没有针对这些疾病的治疗目标 批准的药物。申请人提出心脏是内分泌器官的概念，这是 合成ANP和BNP。释放后，ANP和BNP与心脏高表达的PGC-A结合， 肾脏和血管系统，并产生其第二信使，cGMP。PGC-A/cGMP检测的意义 血压和心血管动态平衡中的通路由其生物学作用所支持，包括血管扩张、钠尿、 利尿、抑制肥大、纤维化、细胞凋亡和炎症，以及抑制醛固酮。AS RH患者的治疗具有挑战性，并且具有最高风险的不良结果，多向作用使 PGC-A作为治疗心血管疾病的新分子靶点。到目前为止，还没有小分子PGC-A刺激物 存在着。通过前期R01资助，我们首次发现了PGC-A/cGMP小分子支架 它们的作用是正变构调节剂(PAM)，它是我们的热门支架MCUF-651的有效衍生物， 是经过精心设计的。初步研究表明MCUF-651：1)增强ANP/PGC-A介导的cGMP 2)增强PGC-A与ANP的结合；3)升高cGMP 并能降低自发性高血压大鼠(SHR)的血压，4)口服生物利用度。在此，我们建议 促进我们对小分子PGC-A细胞保护和降血压作用的生物学理解 利用原型MCUF-651进行正变构调节，并追求药物发现策略来识别 一个优化的小分子PGC-A PAM临床候选，建立在MCUF-651的基础上。目标1：在体外定义 MCUF651‘S对pGC-A/cGMP介导的细胞凋亡和增殖抑制的保护作用 人心肾细胞，人肾上腺细胞中醛固酮的抑制，人冠状动脉的减少 动脉内皮细胞通透性和血管松弛。目的2：在活体内建立慢性心肾 口服MCUF-651对SHR的保护、RAAS抑制和降压作用。目标3：实现 使用迭代循环对MCUF-651进行引线优化，以提高效力和药理特性 药物化学、选择性图谱、功能增强和体外吸收、分布、代谢 和排泄物研究。目的4：评估MCUF-651的代谢负荷，并在随后的研究中 优化铅(S)体内剂量依赖性药代动力学测定及慢性口服疗效观察 在SHR中进行研究，并宣布一种用于IND研究的一流小分子PGC-A刺激器。