{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T21:25:02Z","timestamp":1792531502414,"version":"4.5.0"},"reference-count":91,"publisher":"Canadian Science Publishing","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/deed.en_GB"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["203814\/Z\/16\/A"],"award-info":[{"award-number":["203814\/Z\/16\/A"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Astra Zeneca"}],"content-domain":{"domain":["cdnsciencepub.com"],"crossmark-restriction":false},"short-container-title":["Can. J. Physiol. Pharmacol."],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:p>\n                    Endothelin\u20131 (ET\u20131) was discovered in 1988, followed by identification of ET\n                    <jats:sub>A<\/jats:sub>\n                    and ET\n                    <jats:sub>B<\/jats:sub>\n                    receptors in 1990, enabling rapid development of the first endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) for pulmonary arterial hypertension, a condition marked by elevated ET\u20131. Nearly a decade later, a new therapeutic wave began with the ET\n                    <jats:sub>B<\/jats:sub>\n                    agonist sovateltide (2021) for cerebral ischemic stroke, demonstrating the benefits of ET\n                    <jats:sub>B<\/jats:sub>\n                    activation. More recent antagonist development has shifted toward ET\n                    <jats:sub>A<\/jats:sub>\n                    \u2013selective agents to preserve ET\n                    <jats:sub>B<\/jats:sub>\n                    function. Clazosentan (ET\n                    <jats:sub>A<\/jats:sub>\n                    ) for cerebral vasospasm and aprocitentan (ET\n                    <jats:sub>A<\/jats:sub>\n                    \/ET\n                    <jats:sub>B<\/jats:sub>\n                    ) for resistant hypertension extended endothelin\u2013targeted therapy into more common diseases. In kidney disease, sparsentan (AT\n                    <jats:sub>1<\/jats:sub>\n                    \/ET\n                    <jats:sub>A<\/jats:sub>\n                    ) and atrasentan (ET\n                    <jats:sub>A<\/jats:sub>\n                    ) have both been approved for IgA nephropathy, with atrasentan succeeding after earlier failed trials. Repurposing has become a major strategy in G protein\u2013coupled receptor drug development. This review outlines approaches for identifying legacy endothelin compounds suitable for new indications, using zibotentan, now combined with dapagliflozin to reduce fluid retention as an example. Kidney disease remains a central focus of current trials, which include new ET\n                    <jats:sub>A<\/jats:sub>\n                    \u2013selective diosuxentan and monoclonal antibody getagozumab, and the ET\n                    <jats:sub>B<\/jats:sub>\n                    peptide antagonist vodudeutentan. The review summarizes recent pharmacology and clinical data and highlights emerging strategies for next\u2013generation endothelin\u2013pathway therapeutics.\n                  <\/jats:p>","DOI":"10.1139\/cjpp-2026-0068","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:04:26Z","timestamp":1781877866000},"page":"1-16","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Next-generation therapeutics and renaissance of legacy drugs targeting the endothelin system"],"prefix":"10.1139","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2096-3117","authenticated-orcid":false,"given":"Anthony P.","family":"Davenport","sequence":"first","affiliation":[{"name":"University of Cambridge, Addenbrooke's Hospital","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Anwar","sequence":"additional","affiliation":[{"name":"University of Cambridge, Addenbrooke's Hospital","place":["UK"]},{"name":"Royal Papworth Hospital","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-1602","authenticated-orcid":false,"given":"Rhoda E.","family":"Kuc","sequence":"additional","affiliation":[{"name":"University of Cambridge, Addenbrooke's Hospital","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6698-6757","authenticated-orcid":false,"given":"Lena","family":"Brynne","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0915-5070","authenticated-orcid":false,"given":"Anne-Kristina","family":"Mercier","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2053-3413","authenticated-orcid":false,"given":"Magnus","family":"\u00c5strand","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2529-4477","authenticated-orcid":false,"given":"Peter J","family":"Greasley","sequence":"additional","affiliation":[{"name":"Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2978-1886","authenticated-orcid":false,"given":"Philip","family":"Ambery","sequence":"additional","affiliation":[{"name":"BioPharmaceuticals R&D, AstraZeneca","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9254-7040","authenticated-orcid":false,"given":"Janet J.","family":"Maguire","sequence":"additional","affiliation":[{"name":"University of Cambridge, Addenbrooke's Hospital","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"155","reference":[{"key":"refg1\/ref1","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-023-00347-2"},{"key":"refg2\/ref2","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-025-04429-5"},{"key":"refg3\/ref3","doi-asserted-by":"publisher","DOI":"10.1042\/CS20240605"},{"key":"refg4\/ref4","author":"Anwar M.","year":"2026","journal-title":"Front. Pharmacol"},{"key":"refg5\/ref5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00590-0"},{"key":"refg6\/ref6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.05.044"},{"key":"refg7\/ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2023.105509"},{"key":"refg8\/ref8","doi-asserted-by":"publisher","DOI":"10.1038\/nm1699"},{"key":"refg9\/ref9","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2011.624204"},{"key":"refg10\/ref10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2012.12.004"},{"key":"refg11\/ref11","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.011833"},{"key":"refg12\/ref12","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013080830"},{"key":"refg13\/ref13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.10.045"},{"key":"refg14\/ref14","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-024-02053-0"},{"key":"refg15\/ref15","doi-asserted-by":"publisher","DOI":"10.1111\/imj.12007"},{"key":"refg16\/ref16","doi-asserted-by":"publisher","DOI":"10.3171\/2022.2.JNS212914"},{"issue":"1","key":"refg17\/ref17","first-page":"77","volume":"20","author":"Eriksson C.","year":"2011","journal-title":"J. Gastrointestin. Liver Dis."},{"key":"refg18\/ref18","doi-asserted-by":"publisher","DOI":"10.1021\/tx4001144"},{"key":"refg19\/ref19","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.12919"},{"key":"refg20\/ref20","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2024.2328816"},{"key":"refg21\/ref21","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.4149"},{"key":"refg22\/ref22","doi-asserted-by":"publisher","DOI":"10.1002\/bcp.70332"},{"key":"refg23\/ref23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2025.03.024"},{"key":"refg24\/ref24","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-024-02121-5"},{"key":"refg25\/ref25","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-020-00783-9"},{"key":"refg26\/ref26","doi-asserted-by":"publisher","DOI":"10.33549\/physiolres.933859"},{"key":"refg27\/ref27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.049"},{"key":"refg28\/ref28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaf1067"},{"key":"refg29\/ref29","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12030511"},{"key":"refg30\/ref30","unstructured":"He K., Gao X., Liu C., Zhang Z. 2023. Medical application of pyrimidine sulfonamide derivatives European Patent EP3851435B1 2023 Aug 9. Available from https:\/\/patentimages.storage.googleapis.com\/6c\/33\/a2\/c203dad989fbc7\/EP3851435B1.pdf [accessed April 2026]."},{"key":"refg31\/ref31","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.0000000553"},{"key":"refg32\/ref32","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfad183"},{"key":"refg33\/ref33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2024.10.004"},{"key":"refg34\/ref34","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2409415"},{"key":"refg35\/ref35","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.0000000538"},{"key":"refg36\/ref36","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02230-4"},{"key":"refg37\/ref37","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2020.09.026"},{"key":"refg38\/ref38","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30772-X"},{"key":"refg39\/ref39","volume-title":"LiverTox: clinical and research information on drug-induced liver injury [Internet], Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-","author":"Hoofnagle J.H.","year":"2026"},{"key":"refg40\/ref40","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-024-00705-9.PMID"},{"key":"refg41\/ref41","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac237"},{"key":"refg42\/ref42","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.81.suppl_1.19"},{"key":"refg43\/ref43","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-SITC2023.1527"},{"key":"refg44\/ref44","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01922-4"},{"key":"refg45\/ref45","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-025-02208-7"},{"key":"refg46\/ref46","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.220491"},{"key":"refg47\/ref47","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15103"},{"key":"refg48\/ref48","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010080869"},{"key":"refg49\/ref49","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13750"},{"key":"refg50\/ref50","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-025-01139-y"},{"key":"refg51\/ref51","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70108-9"},{"key":"refg52\/ref52","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.648980"},{"key":"refg53\/ref53","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.108.519942"},{"key":"refg54\/ref54","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12874"},{"key":"refg55\/ref55","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009060593"},{"key":"refg56\/ref56","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-024-01950-2"},{"key":"refg57\/ref57","doi-asserted-by":"publisher","DOI":"10.3171\/2024.4.JNS232191"},{"key":"refg58\/ref58","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-023-01306-7"},{"key":"refg59\/ref59","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3362"},{"key":"refg60\/ref60","doi-asserted-by":"publisher","DOI":"10.1038\/pcan.2013.2"},{"key":"refg61\/ref61","doi-asserted-by":"publisher","DOI":"10.1021\/jm058225d"},{"key":"refg62\/ref62","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602676"},{"key":"refg63\/ref63","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.124.069901"},{"key":"refg64\/ref64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2020.07.007"},{"key":"refg65\/ref65","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.27674"},{"issue":"4","key":"refg66\/ref66","first-page":"Supplement: S17","volume":"9","author":"Noronha I.L.","year":"2024","journal-title":"Int. Rep."},{"key":"refg67\/ref67","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)12297-0"},{"key":"refg68\/ref68","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13051337"},{"key":"refg69\/ref69","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-013-0156-6"},{"key":"refg70\/ref70","doi-asserted-by":"publisher","DOI":"10.1007\/s10143-024-03173-7"},{"key":"refg71\/ref71","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2021.11.027"},{"key":"refg72\/ref72","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23063146"},{"key":"refg73\/ref73","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-69673-w"},{"key":"refg74\/ref74","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.125.25563"},{"key":"refg75\/ref75","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02302-4"},{"key":"refg76\/ref76","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02034-7"},{"key":"refg77\/ref77","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2023-076161"},{"key":"refg78\/ref78","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-024-00908-z"},{"key":"refg79\/ref79","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2025n7x3kgpw"},{"key":"refg80\/ref80","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2025n7x3kgpw"},{"key":"refg81\/ref81","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-022-02818-6"},{"key":"refg82\/ref82","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46015-2"},{"key":"refg83\/ref83","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6904-11-3"},{"key":"refg84\/ref84","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2024.2319132"},{"key":"refg85\/ref85","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfad078"},{"key":"refg86\/ref86","doi-asserted-by":"publisher","DOI":"10.1111\/dom.16468"},{"key":"refg87\/ref87","volume-title":"Clinical adverse effects of endothelin receptor antagonists: insights from the meta-analysis of 4894 patients from 24 randomized double-blind","author":"Wei A.","year":"2016"},{"key":"refg88\/ref88","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.0000000656"},{"key":"refg89\/ref89","first-page":"15","volume":"1","author":"Zhang C.","year":"2021","journal-title":"Int. J. Cardiol. Res."},{"key":"refg90\/ref90","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.118.252700"},{"key":"refg91\/ref91","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.13481"}],"container-title":["Canadian Journal of Physiology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdnsciencepub.com\/doi\/full-xml\/10.1139\/cjpp-2026-0068","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdnsciencepub.com\/doi\/pdf\/10.1139\/cjpp-2026-0068","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:04:30Z","timestamp":1781877870000},"score":1,"resource":{"primary":{"URL":"https:\/\/cdnsciencepub.com\/doi\/10.1139\/cjpp-2026-0068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,1]]},"references-count":91,"alternative-id":["10.1139\/cjpp-2026-0068"],"URL":"https:\/\/doi.org\/10.1139\/cjpp-2026-0068","relation":{},"ISSN":["0008-4212","1205-7541"],"issn-type":[{"value":"0008-4212","type":"print"},{"value":"1205-7541","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,1]]},"assertion":[{"value":"2026-06-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}