{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:09:37Z","timestamp":1779188977595,"version":"3.51.4"},"reference-count":22,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82404424"],"award-info":[{"award-number":["82404424"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Gout and hyperuricemia, prevalent metabolic disorders, are driven by elevated serum uric acid (UA) levels and subsequent monosodium urate crystal deposition, which provoke inflammatory responses and joint damage. Current therapeutic options remain unsatisfactory, underscoring the urgent need for novel agents with improved efficacy and safety profiles. In this study, we aimed to discover a new lead compound capable of concurrently addressing both hyperuricemia and associated inflammatory pain. Two novel compounds were designed and synthesized, among which\n                    <jats:bold>C2<\/jats:bold>\n                    was identified as a promising candidate. In vitro,\n                    <jats:bold>C2<\/jats:bold>\n                    exhibited potent dual inhibitory activity against transient receptor potential vanilloid 1 (TRPV1)\u2014a key mediator of inflammatory pain signaling\u2014and urate transporter 1 (URAT1), which regulated renal UA reabsorption, with IC\u2085\u2080 values of 78.52\u2009\u00b1\u200914.50\u2009nM and 598.6\u2009\u00b1\u2009115.5\u2009nM, respectively. In vivo, oral administration of\n                    <jats:bold>C2<\/jats:bold>\n                    (20\u2009mg\/kg) significantly reduced serum UA levels in a hyperuricemic mouse model, demonstrating efficacy comparable to dotinurad. Furthermore, in a formalin\u2010induced inflammatory pain model,\n                    <jats:bold>C2<\/jats:bold>\n                    produced dose\u2010dependent antinociceptive effects. Mechanistic investigations revealed that\n                    <jats:bold>C2<\/jats:bold>\n                    suppressed NLRP3 inflammasome activation in THP\u20101 cells, as indicated by reduced IL\u20101\u03b2 secretion. Additionally,\n                    <jats:bold>C2<\/jats:bold>\n                    ameliorated dextran sulfate sodium\u2010induced colitis in mice, accompanied by improved histopathological scores. Collectively, these results establish\n                    <jats:bold>C2<\/jats:bold>\n                    as a multi\u2010target lead compound that acts simultaneously on UA transport, nociceptive signaling, and the NLRP3 inflammasome pathway, providing a strong rationale for its further development as a novel therapeutic strategy for gout and hyperuricemia.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70234","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T05:52:20Z","timestamp":1775713940000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of C2: A Novel Lead Compound for the Treatment of Gout and Hyperuricemia via Multi\u2010Pathway Inhibition"],"prefix":"10.1002","volume":"359","author":[{"given":"Lina","family":"Jing","sequence":"first","affiliation":[{"name":"Department of Comprehensive Surgery The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital) Zhengzhou People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruoyang","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou People's Republic of China"},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy Zhengzhou University Zhengzhou People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Comprehensive Surgery The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital) Zhengzhou People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4015-1754","authenticated-orcid":false,"given":"Chunxia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou People's Republic of China"},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy Zhengzhou University Zhengzhou People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00569-9"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0441-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02098"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-024-01137-1"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01710"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01260"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40744-019-0143-9"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01480"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-025-00779-z"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2024.102870"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.3c07655"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2022.2165911"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114628"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1137822"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.861399"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117649"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-62645-6"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.155"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1109938"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-024-01023-1"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c02883"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.03.011"}],"container-title":["Archiv 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