{"title":"具有 1,2-二硫环戊-3-基基团的 ROCK2 抑制剂的合成及其生物活性","authors":"Ruolin Cao, Fangyu Du, Zhiqiang Liu, Pengcheng Cai, Minggang Qi, Wei Xiao, Xuefei Bao, Guoliang Chen","doi":"10.1039/d4md00438h","DOIUrl":null,"url":null,"abstract":"Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound <strong>DC24</strong> was identified as the optimal hit in enzymatic screening with an IC<small><sub>50</sub></small> value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. <strong>DC24</strong> has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and <strong>DC24</strong> is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 <em>via</em> the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of <strong>DC24</strong> with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, <strong>DC24</strong> at a dose of 5 mg kg<small><sup>−1</sup></small> exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, <strong>DC24</strong> exhibits good safety <em>in vivo</em>.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The synthesis and bioactivities of ROCK2 inhibitors with 1,2-dithiolan-3-yl motif\",\"authors\":\"Ruolin Cao, Fangyu Du, Zhiqiang Liu, Pengcheng Cai, Minggang Qi, Wei Xiao, Xuefei Bao, Guoliang Chen\",\"doi\":\"10.1039/d4md00438h\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound <strong>DC24</strong> was identified as the optimal hit in enzymatic screening with an IC<small><sub>50</sub></small> value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. <strong>DC24</strong> has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and <strong>DC24</strong> is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 <em>via</em> the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of <strong>DC24</strong> with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, <strong>DC24</strong> at a dose of 5 mg kg<small><sup>−1</sup></small> exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, <strong>DC24</strong> exhibits good safety <em>in vivo</em>.\",\"PeriodicalId\":21462,\"journal\":{\"name\":\"RSC medicinal chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1039/d4md00438h\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1039/d4md00438h","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
The synthesis and bioactivities of ROCK2 inhibitors with 1,2-dithiolan-3-yl motif
Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound DC24 was identified as the optimal hit in enzymatic screening with an IC50 value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. DC24 has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and DC24 is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 via the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of DC24 with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, DC24 at a dose of 5 mg kg−1 exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, DC24 exhibits good safety in vivo.