Novel Therapeutics for Cardiovascular Disease

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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.