{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:38:25Z","timestamp":1787902705358,"version":"build-2784847793"},"reference-count":29,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2019,9,25]],"date-time":"2019-09-25T00:00:00Z","timestamp":1569369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["16CVD04"],"award-info":[{"award-number":["16CVD04"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2019,10,17]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Excessive mitochondrial matrix Ca<jats:sup>2+<\/jats:sup> and oxidative stress leads to the opening of a high\u2010conductance channel of the inner mitochondrial membrane referred to as the mitochondrial permeability transition pore (mtPTP). Because mtPTP opening can lead to cell death under diverse pathophysiological conditions, inhibitors of mtPTP are potential therapeutics for various human diseases. High throughput screening efforts led to the identification of a 3\u2010carboxamide\u20105\u2010phenol\u2010isoxazole compounds as mtPTP inhibitors. While they showed nanomolar potency against mtPTP, they exhibited poor plasma stability, precluding their use in in\u2005vivo studies. Herein, we describe a series of structurally related analogues in which the core isoxazole was replaced with a triazole, which resulted in an improvement in plasma stability. These analogues were readily generated using the copper\u2010catalyzed \u201cclick chemistry\u201d. One analogue, <jats:italic>N<\/jats:italic>\u2010(5\u2010chloro\u20102\u2010methylphenyl)\u20101\u2010(4\u2010fluoro\u20103\u2010hydroxyphenyl)\u20101<jats:italic>H<\/jats:italic>\u20101,2,3\u2010triazole\u20104\u2010carboxamide (<jats:bold>TR001<\/jats:bold>), was efficacious in a zebrafish model of muscular dystrophy that results from mtPTP dysfunction whereas the isoxazole isostere had minimal effect.<\/jats:p>","DOI":"10.1002\/cmdc.201900376","type":"journal-article","created":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T01:49:41Z","timestamp":1566179381000},"page":"1771-1782","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Second\u2010Generation Inhibitors of the Mitochondrial Permeability Transition Pore with Improved Plasma Stability"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6795-6344","authenticated-orcid":false,"given":"Justina","family":"\u0160ileikyt\u0117","sequence":"first","affiliation":[{"name":"Vollum Institute Oregon Health and Science University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Devereaux","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Core Oregon Health and Science University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelle","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova  Via Ugo Bassi 58\/B 35131 Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Schiavone","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova  Via Ugo Bassi 58\/B 35131 Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Jones","sequence":"additional","affiliation":[{"name":"Vollum Institute Oregon Health and Science University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Nilsen","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Core Oregon Health and Science University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Bernardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova  Via Ugo Bassi 58\/B 35131 Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Forte","sequence":"additional","affiliation":[{"name":"Vollum Institute Oregon Health and Science University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7636-4156","authenticated-orcid":false,"given":"Michael S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Chemical Physiology and Biochemistry Oregon Health and Science University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,25]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00046.2007"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2008.12.011"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2006.05213.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470725207.ch11"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2728(96)00041-2"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.04.023"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.09.023"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.549634"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217823110"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/3403075"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500089200"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201500284"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201500545"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2010.01.003"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol8013528"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)89437-1"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2728(98)00090-5"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2011.08.007"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2016.09.043"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1270"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp126"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610270104"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00316.x"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq126"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu254"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201744705"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002030302"},{"key":"e_1_2_7_28_1","first-page":"4196","author":"Avdesh A.","year":"2012","journal-title":"J. Vis. Exp."},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2017.09.001"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201900376","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.201900376","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201900376","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T13:08:05Z","timestamp":1760274485000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201900376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,25]]},"references-count":29,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2019,10,17]]}},"alternative-id":["10.1002\/cmdc.201900376"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201900376","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,25]]},"assertion":[{"value":"2019-06-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}