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":"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}
引用次数: 0
Abstract
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.