Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators

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.

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

“…At present, GC‐A has become an essential target for treating cardiovascular diseases. 55 CNP activates GC‐B. In failing hearts, the CNP inhibits cardiac remodeling by activating the homologous receptor, GC‐B.…”

“…GC‐A has beneficial properties such as regulating blood pressure and natriuretic, which is activated by two types of NP: ANP and BNP. At present, GC‐A has become an essential target for treating cardiovascular diseases 55 . CNP activates GC‐B.…”

Natriuretic Peptide-Based Novel Therapeutics: Long Journeys of Drug Developments Optimized for Disease States

“…Sangaralingham et al reported the novel discovery of a GC-A receptor modulator in 2022 [ 72 ]. In a cell-based high-throughput screening of the NIH Molecular Libraries Small Molecule Repository (370,620 compounds), GC-A positive allosteric modulator (PAM) scaffolds were identified.…”

“…The MCUF-651 dose-dependent augmentation of cGMP production by ANP was observed in human renal proximal tubular cells, human visceral adipocytes, and human cardiomyocytes. MCUF-651 was orally bioavailable in mice in vivo, and there were enhanced endogenous ANP and BNP ex vivo actions in the plasma of normal subjects and in patients with HT and HF [ 72 ]. Although the direct activator in GC-A or GC-B cells was not found, the GC-A PAM, MCUF-651, has great potential as a novel oral therapeutic.…”

Nanogel Catalysts for the Hydrolysis of Underivatized Disaccharides Identified by a Fast Screening Assay

“…High-throughput screening applying Lipinsky’s “rules of five” in structure–activity relationship studies combined with computational analyses and robotics is a frequently used methodology to identify the most promising compounds during drug discovery of low-molecular-weight targets in a fairly short period of time. The method also allows identification of specific positions in the low-molecular-weight targets for modifications to achieve desired properties, such as water − or fat solubility, − altered binding affinity by the modified strength of H-bonds, − and others.…”