{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:55:03Z","timestamp":1792724103804,"version":"4.5.0"},"reference-count":31,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic & Medicinal Chemistry"],"published-print":{"date-parts":[[2025,2]]},"DOI":"10.1016\/j.bmc.2024.118042","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T01:44:18Z","timestamp":1733967858000},"page":"118042","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":7,"special_numbering":"C","title":["Discovery of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (ASP0965): A potent, orally active and brain-penetrable NLRP3 inflammasome inhibitor with a novel scaffold for the treatment of \u03b1-synucleinopathy"],"prefix":"10.1016","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9250-2441","authenticated-orcid":false,"given":"Yusuke","family":"Inagaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kamikubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikumi","family":"Kuriwaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Yamaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiko","family":"Iida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Tomita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Kakefuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Kurokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Kiso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Saba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Koike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmc.2024.118042_b0005","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nm.3893","article-title":"Inflammasomes: mechanism of action, role in disease, and therapeutics","volume":"21","author":"Guo","year":"2015","journal-title":"Nat Med"},{"key":"10.1016\/j.bmc.2024.118042_b0010","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1038\/sj.cdd.4402194","article-title":"The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation","volume":"14","author":"Fernandes-Alnemri","year":"2007","journal-title":"Cell Death Differ"},{"key":"10.1016\/j.bmc.2024.118042_b0015","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1128\/IAI.73.4.1907-1916.2005","article-title":"Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells","volume":"73","author":"Fink","year":"2005","journal-title":"Infect Immun"},{"key":"10.1016\/j.bmc.2024.118042_b0020","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"10.1016\/j.bmc.2024.118042_b0025","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nature04515","article-title":"Cryopyrin activates the inflammasome in response to toxins and ATP","volume":"440","author":"Mariathasan","year":"2006","journal-title":"Nature"},{"key":"10.1016\/j.bmc.2024.118042_b0030","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature04516","article-title":"Gout-associated uric acid crystals activate the NALP3 inflammasome","volume":"440","author":"Martinon","year":"2006","journal-title":"Nature"},{"key":"10.1016\/j.bmc.2024.118042_b0035","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/nature08938","article-title":"NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals","volume":"464","author":"Duewell","year":"2010","journal-title":"Nature"},{"key":"10.1016\/j.bmc.2024.118042_b0040","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0055375","article-title":"Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies","volume":"8","author":"Codolo","year":"2013","journal-title":"PLoS One"},{"key":"10.1016\/j.bmc.2024.118042_b0045","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/ng756","article-title":"Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome","volume":"29","author":"Hoffman","year":"2001","journal-title":"Nat Genet"},{"key":"10.1016\/j.bmc.2024.118042_b0050","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/s41583-018-0055-7","article-title":"Inflammasome signalling in brain function and neurodegenerative disease","volume":"19","author":"Heneka","year":"2018","journal-title":"Nat Rev Neurosci"},{"key":"10.1016\/j.bmc.2024.118042_b0055","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/nrd.2018.97","article-title":"Targeting the NLRP3 inflammasome in inflammatory diseases","volume":"17","author":"Mangan","year":"2018","journal-title":"Nat Rev Drug Discov"},{"key":"10.1016\/j.bmc.2024.118042_b0060","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"10.1016\/j.bmc.2024.118042_b0065","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nm.3806","article-title":"A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases","volume":"21","author":"Coll","year":"2015","journal-title":"Nat Med"},{"key":"10.1016\/j.bmc.2024.118042_b0070","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/s41589-019-0277-7","article-title":"MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition","volume":"15","author":"Coll","year":"2019","journal-title":"Nat Chem Biol"},{"key":"10.1016\/j.bmc.2024.118042_b0075","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3000354","article-title":"MCC950\/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition","volume":"17","author":"Vande Walle","year":"2019","journal-title":"PLoS Biol"},{"key":"10.1016\/j.bmc.2024.118042_b0080","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41589-019-0278-6","article-title":"MCC950 closes the active conformation of NLRP3 to an inactive state","volume":"15","author":"Tapia-Abellan","year":"2019","journal-title":"Nat Chem Biol"},{"key":"10.1016\/j.bmc.2024.118042_b0085","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/s41586-022-04467-w","article-title":"Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3","volume":"604","author":"Hochheiser","year":"2022","journal-title":"Nature"},{"key":"10.1016\/j.bmc.2024.118042_b0090","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2121353119","article-title":"Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation","volume":"119","author":"Ohto","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.bmc.2024.118042_b0095","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1124\/pharmrev.120.000171","article-title":"Pharmacological inhibition of the nod-like receptor family pyrin domain containing 3 inflammasome with MCC950","volume":"73","author":"Corcoran","year":"2021","journal-title":"Pharmacol Rev"},{"key":"10.1016\/j.bmc.2024.118042_b0100","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aah4066","article-title":"Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice","volume":"10","author":"Gordon","year":"2018","journal-title":"Sci Transl Med"},{"key":"10.1016\/j.bmc.2024.118042_b0105","doi-asserted-by":"crossref","first-page":"14447","DOI":"10.1021\/acs.jmedchem.3c01370","article-title":"Recent progress and prospects of small molecules for NLRP3 inflammasome inhibition","volume":"66","author":"Li","year":"2023","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmc.2024.118042_b0110","doi-asserted-by":"crossref","unstructured":"OECD: Test No. 432: in vitro 3T3 NRU phototoxicity test; 2019. doi: 10.1787\/9789264071162-en.","DOI":"10.1787\/9789264071162-en"},{"key":"10.1016\/j.bmc.2024.118042_b0115","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1016\/j.bmc.2015.04.052","article-title":"Addressing phototoxicity observed in a novel series of biaryl derivatives: discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436","volume":"23","author":"Hamaguchi","year":"2015","journal-title":"Bioorg Med Chem"},{"key":"10.1016\/j.bmc.2024.118042_b0120","doi-asserted-by":"crossref","first-page":"9325","DOI":"10.1021\/jacs.7b04457","article-title":"CF(2)H, a hydrogen bond donor","volume":"139","author":"Sessler","year":"2017","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmc.2024.118042_b0125","doi-asserted-by":"crossref","first-page":"885","DOI":"10.4155\/fmc.14.50","article-title":"Conformational restriction: an effective tactic in 'follow-on'-based drug discovery","volume":"6","author":"Fang","year":"2014","journal-title":"Future Med Chem"},{"key":"10.1016\/j.bmc.2024.118042_b0130","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.nbd.2018.09.005","article-title":"Motor neuron loss and neuroinflammation in a model of alpha-synuclein-induced neurodegeneration","volume":"120","author":"Sorrentino","year":"2018","journal-title":"Neurobiol Dis"},{"key":"10.1016\/j.bmc.2024.118042_b0135","unstructured":"Maestro, version 13.2. New York, NY: Schrodinger, LLC; 2022."},{"key":"10.1016\/j.bmc.2024.118042_b0140","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1007\/BF02797469","article-title":"The origin and characteristics of a pig kidney cell strain, LLC-PK","volume":"12","author":"Hull","year":"1976","journal-title":"In Vitro"},{"key":"10.1016\/j.bmc.2024.118042_b0145","doi-asserted-by":"crossref","first-page":"24248","DOI":"10.1016\/S0021-9258(18)35757-0","article-title":"Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone","volume":"267","author":"Ueda","year":"1992","journal-title":"J Biol Chem"},{"key":"10.1016\/j.bmc.2024.118042_b0150","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/S0022-3565(25)10423-0","article-title":"Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1)","volume":"263","author":"Tanigawara","year":"1992","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1016\/j.bmc.2024.118042_b0155","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0960-8966(03)00031-2","article-title":"Consequence of parvalbumin deficiency in the mdx mouse: histological, biochemical and mechanical phenotype of a new double mutant","volume":"13","author":"Raymackers","year":"2003","journal-title":"Neuromuscul Disord"}],"container-title":["Bioorganic & Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089624004565?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089624004565?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T12:57:32Z","timestamp":1762347452000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0968089624004565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":31,"alternative-id":["S0968089624004565"],"URL":"https:\/\/doi.org\/10.1016\/j.bmc.2024.118042","relation":{},"ISSN":["0968-0896"],"issn-type":[{"value":"0968-0896","type":"print"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Discovery of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (ASP0965): A potent, orally active and brain-penetrable NLRP3 inflammasome inhibitor with a novel scaffold for the treatment of \u03b1-synucleinopathy","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmc.2024.118042","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"118042"}}