{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:57:10Z","timestamp":1790567830087,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:p>\n                    The acid\u2010sensing ion channel 3 (ASIC3) is a neuronal voltage\u2010insensitive Na\n                    <jats:sup>+<\/jats:sup>\n                    channel located in the peripheral nervous system (PNS) and activated by extracellular H\n                    <jats:sup>+<\/jats:sup>\n                    , that is dysregulated in peripheral neuropathic pain. ASIC3 was found in stem cells of central nervous system (CNS)\u2013located glioblastoma multiforme (GBM CSCs), and its chronic activation kills dysfunctional GBM CSCs without any effect on ASIC3\u2010lacking CNS tissues. We rationally designed and synthesized blood\u2013brain barrier (BBB)\u2013compliant analogues of GMQ, a known guanidyl quinazoline ASIC3 activator; we replaced its guanidine group with a guanyl hydrazone (GH) and carried out scaffold substitutions and other structural variations in 16 GMQ analogues to establish a structure\u2013activity relationship (SAR). Our more potent GH analogue\n                    <jats:bold>1a<\/jats:bold>\n                    showed specific activity against GBM CSC neurospheres, coupled with a better safety profile on mammalian nontumor cells and a better brain\u2010to\u2010plasma ratio compared with GMQ. Such results provide valuable insights for further structural optimization of heteroaryl GHs as ASIC3 modulators.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70438","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T02:23:24Z","timestamp":1790216604000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Blood\u2013Brain Barrier\u2010Permeable Guanylhydrazone Analogue of the ASIC3 Activator GMQ Inhibits Human Glioblastoma Stem Cell Growth In Vitro"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5662-4747","authenticated-orcid":false,"given":"Leonardo","family":"Maiorana","sequence":"first","affiliation":[{"name":"Chemistry Department Universit\u00e0 degli Studi di Milano \u2013 La Statale  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1212-143X","authenticated-orcid":false,"given":"Nicoletta","family":"Collura","sequence":"additional","affiliation":[{"name":"Experimental Imaging Centre IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3110-7233","authenticated-orcid":false,"given":"Andrea","family":"Gotti","sequence":"additional","affiliation":[{"name":"Chemistry Department Universit\u00e0 degli Studi di Milano \u2013 La Statale  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"De Leonardis","sequence":"additional","affiliation":[{"name":"Experimental Imaging Centre IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0311-1721","authenticated-orcid":false,"given":"Greta","family":"Donati","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Universit\u00e0 degli Studi di Napoli Federico Secondo  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5499-4045","authenticated-orcid":false,"given":"Alice","family":"Maiocchi","sequence":"additional","affiliation":[{"name":"Chemistry Department Universit\u00e0 degli Studi di Milano \u2013 La Statale  Milan Italy"},{"name":"Olon SpA  Segrate Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Marinelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Universit\u00e0 degli Studi di Napoli Federico Secondo  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2396-756X","authenticated-orcid":false,"given":"Andrea","family":"Menegon","sequence":"additional","affiliation":[{"name":"Experimental Imaging Centre IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9709-7344","authenticated-orcid":false,"given":"Pierfausto","family":"Seneci","sequence":"additional","affiliation":[{"name":"Chemistry Department Universit\u00e0 degli Studi di Milano \u2013 La Statale  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.02.005"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP278707"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3529"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2021.09.008"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2017.02.001"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2015.01.005"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-023-02902-z"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13666-9"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-71623-9"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2025.2463357"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.09.001"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.5c00463"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01437"},{"key":"e_1_2_8_15_1","first-page":"1343","volume-title":"Foye's Principles of Medicinal Chemistry","author":"Foye W. O.","year":"2008"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1601"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(85)90179-0"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/jr9320001875"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3OB02067C"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2022.133412"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.32.2005"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae254"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117575"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-026-35496-4"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm051256o"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.239558"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.113834"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1389440"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0056-x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3OB02067C"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-018-0248-7"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-2730"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-1364"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep44843"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25782"},{"key":"e_1_2_8_37_1","volume-title":"Schr\u00f6dinger Release 2025\u20102: Maestro","author":"Schr\u00f6dinger, LLC","year":"2025"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-013-9644-8"},{"key":"e_1_2_8_39_1","volume-title":"Protein Preparation Workflow; Epik","year":"2025"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct100578z"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.1c00302"},{"key":"e_1_2_8_42_1","volume-title":"LigPrep","year":"2025"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.3c00044"},{"key":"e_1_2_8_44_1","volume-title":"Epik","year":"2025"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.1c00810"},{"key":"e_1_2_8_46_1","volume-title":"Glide","year":"2025"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.6b01258"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5RA05574A"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00075"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2091-7-18"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv\u20102024\u20108489b"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1039\/c5pp00349k"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201405852"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.3c03392"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17288"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70438","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70438","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70438","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:40:32Z","timestamp":1790566832000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":54,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,9,28]]}},"alternative-id":["10.1002\/cmdc.70438"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70438","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"assertion":[{"value":"2026-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70438"}}