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T.; St. Jean, D. J., Jr. Next-generation small molecule therapies for heart failure: 2015 and beyond. Bioorg Med Chem Lett 2018, 28, 1429\u20131435. DOI: 10.1016\/j.bmcl.2018.03.064.","DOI":"10.1016\/j.bmcl.2018.03.064"},{"key":"10.1016\/j.bmcl.2020.127499_b0020","doi-asserted-by":"crossref","unstructured":"Hauptman, P. J., Kelly, R. A. Digitalis. Cardiac glycosides are another drug class for the treatment of CHF but suffer from myriad side effects. Circulation. 1999, 99, 1265\u20131270. 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Castan-Laurell, I., Masri, B., Valet, P. The apelin\/APJ system as a therapeutic target in metabolic diseases. Expert Opin Ther Tar 2019, 23, 215\u2013225. DOI: 10.1080\/14728222.2019.1561871.","DOI":"10.1080\/14728222.2019.1561871"},{"key":"10.1016\/j.bmcl.2020.127499_b0045","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.regpep.2003.11.002","article-title":"Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells","volume":"118","author":"Kleinz","year":"2004","journal-title":"Regul Pept"},{"key":"10.1016\/j.bmcl.2020.127499_b0050","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1006\/bbrc.1998.9489","article-title":"Isolation and Characterization of a Novel Endogenous Peptide Ligand for the Human APJ Receptor","volume":"251","author":"Tatemoto","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1016\/j.bmcl.2020.127499_b0055","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1139\/bcb-2014-0072","article-title":"The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR","volume":"92","author":"Chapman","year":"2014","journal-title":"Biochem Cell Biol"},{"key":"10.1016\/j.bmcl.2020.127499_b0060","doi-asserted-by":"crossref","unstructured":"ELABELA has also been found as an endogenous ligand for. Chng, A.P.J., Ho, S.C., Tian, L., Reversade, J., Elabela B. a hormone essential for heart development signals via the apelin receptor. Dev Cell 2013, 27, 672\u2013680. DOI: 10.1016\/j.devcel.2013.11.002.","DOI":"10.1016\/j.devcel.2013.11.002"},{"key":"10.1016\/j.bmcl.2020.127499_b0065","doi-asserted-by":"crossref","unstructured":"Toddler has also been found as an endogenous ligand for APJ: Pauli, A.; Norris, M. L.; Valen, E.; Chew, G. L.; Gagnon, J.A.; Zimmerman, S.; Mitchell, A.; Ma, J.; Dubrulle, J.; Reyon, D.; Tsai, S. Q.; Joung, J. K.; Saghatelian, A.; Schier, A. F. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science 2014, 343, 1248636. 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Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 2009, 296, H2007\u2013H2014. 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Kanai, S.; Alex, R.; Belli, S; Donzelli, M.; Benedek, G. B. The molecular basis for the prolonged blood circulation of lipidated incretin peptides: Peptide oligomerization or binding to serum albumin? J Controlled Release 2016, 241, 25\u201333. DOI: 10.1016\/j.jconrel.2016.08.035.","DOI":"10.1016\/j.jconrel.2016.08.035"},{"key":"10.1016\/j.bmcl.2020.127499_b0115","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1021\/mp500519s","article-title":"Transformation of Oligomers of Lipidated Peptide Induced by Change in pH","volume":"12","author":"Wang","year":"2015","journal-title":"Mol Pharm"},{"key":"10.1016\/j.bmcl.2020.127499_b0120","series-title":"Peptides and Peptide-based Biomaterials and their Biomedical Applications. 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DOI: 10.1016\/j.xphs.2018.10.018.","DOI":"10.1016\/j.xphs.2018.10.018"},{"key":"10.1016\/j.bmcl.2020.127499_b0135","unstructured":"We expected that a lipid conjugate with high PPB would be able to access this receptor since APJ is expressed on the surface of endothelial cells in both the heart and the vasculature."},{"key":"#cr-split#-10.1016\/j.bmcl.2020.127499_b0140.1","doi-asserted-by":"crossref","unstructured":"Previous reports of lipidated apelin-13 have been made. Juhl, C., Els-Heindl, S., Sch\u00f6nauer, R., Redlich, G., Haaf, E., Wunder, F., Riedl, B., Burkhardt, N., Beck-Sickinger, A.G., Bierer, D. Development of Potent and Metabolically Stable APJ Ligands with High Therapeutic Potential. ChemMedChem. 2016, 11, 1-8. DOI: 10.1002\/cmdc.201600307. O'Harte, F. P.N., Parthsarathy, V.","DOI":"10.1002\/cmdc.201600307"},{"key":"#cr-split#-10.1016\/j.bmcl.2020.127499_b0140.2","doi-asserted-by":"crossref","unstructured":"Hogg, C., Flatt, P. R. Acylated apelin-13 amide analogues exhibited enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties. Biochem Pharmacol 2017, 146, 165-173. DOI: 10.1016\/j.bcp.2017.10.002.","DOI":"10.1016\/j.bcp.2017.10.002"},{"key":"10.1016\/j.bmcl.2020.127499_b0145","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1161\/HYPERTENSIONAHA.114.05099","article-title":"Design, Characterization, and First-In-Human Study of the Vascular Actions of a Novel Biased Apelin Receptor Agonist","volume":"65","author":"Brame","year":"2015","journal-title":"Hypertension"},{"key":"10.1016\/j.bmcl.2020.127499_b0150","doi-asserted-by":"crossref","unstructured":"This linker was also used in semaglutide: Lau, J., Bloch, P., Sch\u00e4ffer, L., Pettersson, I., Spetzler, J., Kofoed, J., Madsen, K., Knudsen, L. B., McGuire, J., Steensgaard, D. B., Strauss, H. M., Gram, D. X., Knudsen, S. M., Nielsen, F. S., Thygesen, P., Reedtz-Runge, S, Kruse, T. Discovery of the Once-Weekly Glucagon-Like-1 (GLP-1) Analogue Semaglutide. J Med Chem 2015, 58, 7370\u20137380. DOI: 10.1021\/acs.jmedchem.5b00726.","DOI":"10.1021\/acs.jmedchem.5b00726"},{"key":"10.1016\/j.bmcl.2020.127499_b0155","doi-asserted-by":"crossref","unstructured":"The C13 lipid was initially chosen as this showed similar binding to albumin as C16 when conjugated to insulin. Kurtzhals, P., Havelund, S., Jonassen, I., Kiehr, B., Larsen, U. D., Ribel, U., Markussen, J. Albumin binding of insulins acylated with fatty acids: characterization of the ligand-protein interaction and correlation between binding affinity and timing of the insulin effect in vivo. Biochem J 1995, 312, 725\u2013731. DOI: 10.1042\/bj3120725.","DOI":"10.1042\/bj3120725"},{"key":"10.1016\/j.bmcl.2020.127499_b0160","unstructured":"See SI for experimental conditions."},{"key":"10.1016\/j.bmcl.2020.127499_b0165","unstructured":"Also abbreviated as Aeea and AEEAc."},{"key":"10.1016\/j.bmcl.2020.127499_b0170","unstructured":"Percent recovery data for all peptides was either acceptable (75\u201390%) or good (>90%)."},{"key":"10.1016\/j.bmcl.2020.127499_b0175","unstructured":"Pyr-apelin-13 is also a potent, full agonist of the human APJ receptor: human GTP\u03b3S EC50 = 3.11 nM, efficacy = 139%, in-house data."},{"key":"10.1016\/j.bmcl.2020.127499_b0180","unstructured":"2 is also a potent, full agonist of the human APJ receptor: human GTP\u03b3S EC50 = 0.23 nM, efficacy = 116%, in-house data."},{"key":"10.1016\/j.bmcl.2020.127499_b0185","unstructured":"The lower EF at the highest dose vs. the second highest dose of 2 (30 \u03bcg\/kg\/min and 10 \u03bcg\/kg\/min, respectively) may be due to differences in heart rate, vasodilation, rate of infusion, or tissue distribution. MAP transiently decreased during infusions with 1 and 2 triggering heart rate increase at the highest doses, Figure SI-1. MAP recovered for all animals by the end of the studies, Figure SI-2."},{"key":"10.1016\/j.bmcl.2020.127499_b0190","unstructured":"2 was not observed after 30 min; curve shown in Figure SI-3. The in vivo study for 1 was reported to be run for 35 min: Ref 29, Brame, et al."},{"key":"10.1016\/j.bmcl.2020.127499_b0195","unstructured":"Apelin-17: KRRQRPRLSHKGPMPF. rGTP\u03b3S EC50 = 0.7 nM, efficacy = 133%, hGTP\u03b3S EC50 = 0.2 nM, efficacy = 128%; rat plasma, and liver, kidney S9 fractions (percent remaining at 4 h, respectively): <1, 3, 8, in-house data."},{"key":"10.1016\/j.bmcl.2020.127499_b0200","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/bip.22498","article-title":"Stability and Degradation Patterns of Chemically Modified Analogs of Apelin-13 in Plasma and Cerebrospinal Fluid","volume":"102","author":"Murza","year":"2014","journal-title":"Biopolymers"},{"key":"10.1016\/j.bmcl.2020.127499_b0205","unstructured":"Experimental procedure and data in SI."},{"key":"10.1016\/j.bmcl.2020.127499_b0210","unstructured":"Human APJ GTP\u03b3S potency and efficacy trended towards that of rat APJ GTP\u03b3S."},{"key":"10.1016\/j.bmcl.2020.127499_b0215","unstructured":"Conjugation with various lipids and linkages on the sidechain of S70K proved to lower potency into the double and triple digit nanomolar and efficacy into the partial agonist ranges."},{"key":"10.1016\/j.bmcl.2020.127499_b0220","unstructured":"The effect of linkage identity was also examined, Table SI-4, but proved to have little impact on either potency, efficacy, or rPPB."},{"key":"10.1016\/j.bmcl.2020.127499_b0225","unstructured":"Where compared, hPPB was similar, but slightly lower (fu,diff < 1%) than rPPB."},{"key":"10.1016\/j.bmcl.2020.127499_b0230","unstructured":"Cmax,u was used to calculate fold-coverage after an acute improvement in cardiac function was observed in a 30 min infusion of 2."}],"container-title":["Bioorganic &amp; Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X20306107?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X20306107?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T07:36:49Z","timestamp":1760773009000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0960894X20306107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11]]},"references-count":47,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["S0960894X20306107"],"URL":"https:\/\/doi.org\/10.1016\/j.bmcl.2020.127499","relation":{},"ISSN":["0960-894X"],"issn-type":[{"value":"0960-894X","type":"print"}],"subject":[],"published":{"date-parts":[[2020,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Half-life extension of peptidic APJ agonists by N-terminal lipid conjugation","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmcl.2020.127499","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2020 Elsevier Ltd. 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