{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:05:23Z","timestamp":1790301923544,"version":"4.1.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>New heart failure therapies that safely augment cardiac contractility and output are needed. Previous apelin peptide studies have highlighted the potential for APJ (apelin receptor) agonism to enhance cardiac function in heart failure. However, apelin\u2019s short half-life limits its therapeutic utility. Here, we describe the preclinical characterization of a novel, orally bioavailable APJ agonist, BMS-986224.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      BMS-986224 pharmacology was compared with (Pyr\n                      <jats:sup>1<\/jats:sup>\n                      ) apelin-13 using radio ligand binding and signaling pathway assays downstream of APJ (cAMP, phosphorylated ERK [extracellular signal-regulated kinase], bioluminescence resonance energy transfer\u2013based G-protein assays, \u03b2-arrestin recruitment, and receptor internalization). Acute effects on cardiac function were studied in anesthetized instrumented rats. Chronic effects of BMS-986224 were assessed echocardiographically in the RHR (renal hypertensive rat) model of cardiac hypertrophy and decreased cardiac output.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      BMS-986224 was a potent (Kd=0.3 nmol\/L) and selective APJ agonist, exhibiting similar receptor binding and signaling profile to (Pyr\n                      <jats:sup>1<\/jats:sup>\n                      ) apelin-13. G-protein signaling assays in human embryonic kidney 293 cells and human cardiomyocytes confirmed this and demonstrated a lack of signaling bias relative to (Pyr\n                      <jats:sup>1<\/jats:sup>\n                      ) apelin-13. In anesthetized instrumented rats, short-term BMS-986224 infusion increased cardiac output (10%\u201315%) without affecting heart rate, which was similar to (Pyr\n                      <jats:sup>1<\/jats:sup>\n                      ) apelin-13 but differentiated from dobutamine. Subcutaneous and oral BMS-986224 administration in the RHR model increased stroke volume and cardiac output to levels seen in healthy animals but without preventing cardiac hypertrophy and fibrosis, effects differentiated from enalapril.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      We identify a novel, potent, and orally bioavailable nonpeptidic APJ agonist that closely recapitulates the signaling properties of (Pyr\n                      <jats:sup>1<\/jats:sup>\n                      ) apelin-13. We show that oral APJ agonist administration induces a sustained increase in cardiac output in the cardiac disease setting and exhibits a differentiated profile from the renin-angiotensin system inhibitor enalapril, supporting further clinical evaluation of BMS-986224 in heart failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.120.007351","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T05:00:20Z","timestamp":1614920420000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6262-2839","authenticated-orcid":true,"given":"Peter","family":"Gargalovic","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb, Drug Discovery, Princeton, NJ (P.G., P.W., J.O., H.F., T.W., M.Y., E.C., C.X., X.-Q.C., C.G., M.L., R.W., D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8224-7423","authenticated-orcid":true,"given":"Pancras","family":"Wong","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, Drug Discovery, Princeton, NJ (P.G., P.W., J.O., H.F., T.W., M.Y., E.C., C.X., X.-Q.C., C.G., M.L., R.W., D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8128-6885","authenticated-orcid":true,"given":"Joelle","family":"Onorato","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, Drug Discovery, Princeton, NJ (P.G., P.W., J.O., H.F., T.W., M.Y., E.C., C.X., X.-Q.C., C.G., M.L., R.W., D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2309-0136","authenticated-orcid":true,"given":"Heather","family":"Finlay","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, Drug Discovery, Princeton, NJ (P.G., P.W., J.O., H.F., T.W., M.Y., E.C., C.X., X.-Q.C., C.G., M.L., R.W., D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, Drug Discovery, Princeton, NJ (P.G., P.W., J.O., H.F., T.W., M.Y., E.C., C.X., X.-Q.C., C.G., M.L., R.W., D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mujing","family":"Yan","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, Drug Discovery, Princeton, NJ (P.G., P.W., J.O., H.F., T.W., M.Y., E.C., C.X., X.-Q.C., C.G., M.L., R.W., 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