Doretta Cuffaro, Tina Burkhard, Bianca Laura Bernardoni, Riccardo Di Leo, Xiaohan Zhang, Salvatore Galati, Tiziano Tuccinardi, Marco Macchia, Armando Rossello, Salvatore Santamaria, Rens de Groot and Elisa Nuti
{"title":"作为 ADAMTS7 抑制剂的芳基磺酰胺类化合物的设计、合成和生物学评价","authors":"Doretta Cuffaro, Tina Burkhard, Bianca Laura Bernardoni, Riccardo Di Leo, Xiaohan Zhang, Salvatore Galati, Tiziano Tuccinardi, Marco Macchia, Armando Rossello, Salvatore Santamaria, Rens de Groot and Elisa Nuti","doi":"10.1039/D4MD00149D","DOIUrl":null,"url":null,"abstract":"<p >The proteolytic activity of the enzyme ADAMTS7 was recently shown to enhance the progression of atherosclerosis, in line with human genetic findings suggesting that ADAMTS7 has a role in the pathophysiology of coronary heart disease. Targeting the active site of ADAMTS7 with a small molecule inhibitor, therefore, has therapeutic potential. Here, we report the design and synthesis of a novel hydroxamate-based arylsulfonamide that is a potent and selective ADAMTS7 inhibitor. <em>In silico</em> studies guided the hit optimization process aiming to improve selectivity of the previously reported (non-selective) inhibitor EDV33. Our lead compound is a <em>p</em>-trifluoromethyl biphenyl sulfonamide, which displayed a 12-fold selectivity for ADAMTS7 (<em>K</em><small><sub>i</sub></small> = 9 nM) over ADAMTS5 (<em>K</em><small><sub>i</sub></small> = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 (<em>K</em><small><sub>i</sub></small> = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00149d?page=search","citationCount":"0","resultStr":"{\"title\":\"Design, synthesis and biological evaluation of arylsulfonamides as ADAMTS7 inhibitors†\",\"authors\":\"Doretta Cuffaro, Tina Burkhard, Bianca Laura Bernardoni, Riccardo Di Leo, Xiaohan Zhang, Salvatore Galati, Tiziano Tuccinardi, Marco Macchia, Armando Rossello, Salvatore Santamaria, Rens de Groot and Elisa Nuti\",\"doi\":\"10.1039/D4MD00149D\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The proteolytic activity of the enzyme ADAMTS7 was recently shown to enhance the progression of atherosclerosis, in line with human genetic findings suggesting that ADAMTS7 has a role in the pathophysiology of coronary heart disease. Targeting the active site of ADAMTS7 with a small molecule inhibitor, therefore, has therapeutic potential. Here, we report the design and synthesis of a novel hydroxamate-based arylsulfonamide that is a potent and selective ADAMTS7 inhibitor. <em>In silico</em> studies guided the hit optimization process aiming to improve selectivity of the previously reported (non-selective) inhibitor EDV33. Our lead compound is a <em>p</em>-trifluoromethyl biphenyl sulfonamide, which displayed a 12-fold selectivity for ADAMTS7 (<em>K</em><small><sub>i</sub></small> = 9 nM) over ADAMTS5 (<em>K</em><small><sub>i</sub></small> = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 (<em>K</em><small><sub>i</sub></small> = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation.</p>\",\"PeriodicalId\":21462,\"journal\":{\"name\":\"RSC medicinal chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-06-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00149d?page=search\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00149d\",\"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://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00149d","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Design, synthesis and biological evaluation of arylsulfonamides as ADAMTS7 inhibitors†
The proteolytic activity of the enzyme ADAMTS7 was recently shown to enhance the progression of atherosclerosis, in line with human genetic findings suggesting that ADAMTS7 has a role in the pathophysiology of coronary heart disease. Targeting the active site of ADAMTS7 with a small molecule inhibitor, therefore, has therapeutic potential. Here, we report the design and synthesis of a novel hydroxamate-based arylsulfonamide that is a potent and selective ADAMTS7 inhibitor. In silico studies guided the hit optimization process aiming to improve selectivity of the previously reported (non-selective) inhibitor EDV33. Our lead compound is a p-trifluoromethyl biphenyl sulfonamide, which displayed a 12-fold selectivity for ADAMTS7 (Ki = 9 nM) over ADAMTS5 (Ki = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 (Ki = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation.