Abstract: The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.
Competing Interests: Competing interest statement: A patent related to small molecule guanylyl cyclase A receptor enhancers has been filed by the Mayo Foundation for Medical Education and Research and Sanford Burnham Prebys Medical Discovery Institute, of which S.J.S., S. Peddibhotla, P.M.H., H.E.S., P.R.M., S.M., and J.C.B. are listed as inventors, and this technology has been licensed to AlloRock. A patent for the ex vivo human therapeutic potency assay has been also filed by the Mayo Foundation for Medical Education and Research, of which S.J.S., Y.Z., and J.C.B. are listed as inventors. This research is being conducted in compliance with Mayo Clinic conflict of interest policies.
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