Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.
Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.
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发现小分子鸟苷酸环化酶 A 受体正变构调节剂。
DOI：
10.1073/pnas.2109386118
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发表时间：
2021
影响因子：
11.1
通讯作者：
BurnettJr,
中科院分区：
文献类型：
--
作者：
Sangaralingham,SJeson;Whig,Kanupriya;Peddibhotla,Satyamaheshwar;Kirby,RJason;Sessions,HamptonE;Maloney,PatrickR;Hershberger,PaulM;Mose-Yates,Heather;Hood,BeckyL;Vasile,Stefan;Pan,Shuchong;Zheng,Ye;Malany,Siobhan;BurnettJr,
颗粒鸟苷酸环化酶A受体（GC-A）通过其内源性配体心房利钠肽（ANP）和b型利钠肽（BNP）的激活，具有有益的生物学特性，例如血压调节、排钠、抑制不良重塑、抑制肾素-血管紧张素-醛固酮系统，通过产生第二信使环磷酸鸟苷（cGMP）而具有良好的代谢作用。因此，GC-A代表了心血管疾病及其相关危险因素的重要分子治疗靶点。然而，尚未发现口服生物可利用并直接靶向GC-A以增强cGMP的小分子。在这里，我们进行了NIH分子库小分子库的基于细胞的高通量筛选活动，并且我们成功地鉴定了小分子GC-A正变构调节剂（PAM）支架。进一步的药物化学结构-活性关系的铅支架的努力导致了GC-A PAM，MCUF-651的发展，它增强了ANP介导的cGMP在人体心脏，肾脏和脂肪细胞的产生，并抑制心肌细胞肥大在体外。进一步，结合分析证实MCUF-651与GC-A结合并选择性地增强ANP与GC-A的结合。此外，MCUF-651在小鼠中具有口服生物利用度，并增强正常受试者和高血压或心力衰竭患者血浆中发现的内源性ANP和BNP离体产生GC-A介导的cGMP的能力。在这项工作中，我们报告了一种口服小分子GC-A PAM的发现和开发，该PAM具有作为心血管，肾脏和代谢疾病治疗药物的巨大潜力。
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.