{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T08:10:06Z","timestamp":1763021406901,"version":"3.45.0"},"reference-count":31,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Inducible nitric oxide synthase (iNOS) is an attractive target to develop drugs for the treatment of rheumatoid arthritis (RA), whose overexpression leads to the release of abundant NO. In this study, a series of compounds were designed and synthesized bearing the scaffold of 7\n                    <jats:italic>H<\/jats:italic>\n                    \u2010pyrrolo[2,3\u2010\n                    <jats:italic>d<\/jats:italic>\n                    ]pyrimidine to improve CLogP values and in vivo anti\u2010inflammatory activity via molecular hybridization, whose derivatives in a previous study demonstrated good inhibition toward NO production but high CLogP values and weak potency in vivo. Among them,\n                    <jats:bold>N3b<\/jats:bold>\n                    effectively suppressed NO production in a concentration\u2010dependent manner (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20094.66\u2009\u00b1\u20090.19\u2009\u03bcM) in LPS\u2010induced RAW264.7 cells. Mechanically,\n                    <jats:bold>N3b<\/jats:bold>\n                    mildly inhibited the protein expression of iNOS (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200913.60\u2009\u00b1\u20090.39\u2009\u03bcM), without remarkable influence on the mRNA levels of iNOS or other classical pro\u2010inflammatory cytokines including IL\u20101\u03b2, IL\u20106, and TNF\u2010\u03b1 at the high concentration of 30\u2009\u00b5M. With favorable drug\u2010likeness,\n                    <jats:bold>N3b<\/jats:bold>\n                    significantly alleviated paw edema at the dose of 30\u2009mg\/kg in the acute inflammation model and mitigated paw swelling and joint damage at a dosage of 10\u2009mg\/kg in the chronic arthritis model. Furthermore,\n                    <jats:bold>N3b<\/jats:bold>\n                    did not cause any obvious weight loss and pathological changes of important organs in treated mice, indicating that\n                    <jats:bold>N3b<\/jats:bold>\n                    is a potent candidate iNOS inhibitor for the treatment of RA.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70038","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T15:25:29Z","timestamp":1752074729000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structural Optimizations on the Scaffold of 7\n                    <i>H<\/i>\n                    \u2010Pyrrolo[2,3\u2010\n                    <i>d<\/i>\n                    ]Pyrimidine to Develop Potent iNOS Inhibitors With Improved Antiarthritis Activity In Vivo"],"prefix":"10.1002","volume":"358","author":[{"given":"Wenchu","family":"Wang","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"},{"name":"Key Laboratory of Basic Research on Regional Diseases, College of Basic Medical Science Guangxi Medical University Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingsheng","family":"Qin","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianjing","family":"Feng","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyang","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Ling","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Xie","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanqin","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayuan","family":"Luo","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous Region, Pharmaceutical College Guangxi Medical University, Nanning Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sisi","family":"Cao","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Key Laboratory of Micro\u2010Nanoscale Bioanalysis and Drug Screening, Education Department of Guangxi Zhuang Autonomous 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