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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,12,28]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>The particulate guanylyl cyclase A receptor (GC-A), via its endogenous cardiac-derived hormones atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), plays a pivotal role in maintaining intravascular volume, arterial pressure, cardiovascular structure, function, and, more recently, metabolic homeostasis. As such, therapies to potentiate GC-A signaling via peptide augmentation have yielded promising results in clinical trials. A major breakthrough in GC-A therapeutics would be a small molecule that sensitizes the GC-A receptor to endogenous ANP or BNP, which to date does not exist. Here, we report the development of an orally bioavailable, small molecule positive allosteric modulator of GC-A that exhibits therapeutic activity in human hypertension and heart failure ex vivo.<\/jats:p>","DOI":"10.1073\/pnas.2109386118","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T16:26:07Z","timestamp":1640017567000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators"],"prefix":"10.1073","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3967-8703","authenticated-orcid":false,"given":"S. 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