Novel Therapeutics for Cardiovascular Disease

心血管疾病的新疗法

• 批准号: 10621236
• 负责人: Siobhan Malany
• 金额: $ 69.34万
• 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/10621236
• 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; 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; Oral Administration; Particulate; Pathway interactions; Patients; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Production; Proliferating; 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; 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; pharmacologic; 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.

项目摘要 该应用是要推进范例变度，特别是Guanylyl循环酶A受体（PGC-A）和3'，5'环状 鸟苷单磷酸（CGMP）疗法，并开发了第一类小分子靶向 心血管疾病（CVD）的PGC-A/CGMP途径。我们的简历重点是未满足新颖的临床需求 高血压治疗靶标（HTN），特别是耐药性高血压（RH），没有 批准的药物。申请人提出了一个概念，即心脏是内分泌器官 合成ANP和BNP。释放后，ANP和BNP与PGC-A结合，在心脏中高度表达， 肾脏和脉管系统，并产生其第二个使者CGMP。 PGC-A/CGMP的意义 BP和CV稳态中的途径得到了其生物学作用的支持，包括血管舒张，Natriuresis， 利尿，肥大，纤维化，细胞凋亡和注射以及醛固酮的抑制作用。 RH患者受到挑战以治疗和风险最高 PGC-A是CV治疗的新型分子靶标。迄今为止，没有小分子PGC-A刺激器 存在。通过先前的R01资金，我们首次发现PGC-A/CGMP小分子支架 哪个功能充当阳性变构调节剂（PAM），我们的命中支架的潜在衍生物MCUF-651， 被设计了。初步研究表明，MCUF-651：1）电位ANP/PGC-A介导的CGMP 在体外产生和减少心肌细胞肥大； 2）增强PGC-A的ANP结合； 3）提高CGMP 自发性高血压大鼠（SHR）和4）的BP降低，是可生物利用的。在此，我们建议 通过小分子PGC-A提高我们对细胞保护和BP降低作用的生物学理解 利用原型MCUF-651并购买药物发现策略以识别原型的积极变构调节 优化的小分子PGC-A PAM临床候选者，在MCUF-651建造。目标1：在体外定义， MCUF-651对PGC-A/CGMP的细胞保护作用介导的抑制凋亡和增殖的抑制 人心脏细胞，人肾上腺细胞中醛固酮的抑制作用，人类冠状动脉的减少 动脉中的内皮细胞渗透性和血管延缓。目标2：在体内建立慢性心脏 保护性，抑制RAAS和BP降低SHR口服MCUF-651的作用。目标3：到 使用迭代周期进行MCUF-651的铅优化以提高效力和药物特性 药物化学，选择性分析，功能增强和体外抽象，分布，代谢 和极端研究。目标4：评估MCUF-651的代谢责任，然后再进步 优化优化的铅（S）在体内剂量依赖性药代动力学测量和慢性口服效率 在SHR中进行研究，并宣布一类小分子PGC-A刺激剂进行辅助研究。