Cuffaro Doretta, Burkhard Tina, Bernardoni Bianca Laura, Di Leo Riccardo, Zhang Xiaohan, Galati Salvatore, Tuccinardi Tiziano, Macchia Marco, Rossello Armando, Santamaria Salvatore, de Groot Rens, Nuti Elisa
Department of Pharmacy, University of Pisa Via Bonanno 6 56126 Pisa Italy
Department of Biochemical and Physiological Sciences, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey Edward Jenner Building Guildford GU2 7XH UK
RSC Med Chem. 2024 Jun 19;15(8):2806-2825. doi: 10.1039/d4md00149d. eCollection 2024 Aug 14.
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. studies guided the hit optimization process aiming to improve selectivity of the previously reported (non-selective) inhibitor EDV33. Our lead compound is a -trifluoromethyl biphenyl sulfonamide, which displayed a 12-fold selectivity for ADAMTS7 ( = 9 nM) over ADAMTS5 ( = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 ( = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation.
最近研究表明，酶ADAMTS7的蛋白水解活性会促进动脉粥样硬化的发展，这与人类遗传学研究结果一致，表明ADAMTS7在冠心病的病理生理学中起作用。因此，用小分子抑制剂靶向ADAMTS7的活性位点具有治疗潜力。在此，我们报告了一种新型异羟肟酸基芳基磺酰胺的设计与合成，该化合物是一种强效且选择性的ADAMTS7抑制剂。研究指导了命中优化过程，旨在提高先前报道的（非选择性）抑制剂EDV33的选择性。我们的先导化合物是一种α-三氟甲基联苯磺酰胺，它对ADAMTS7（IC50 = 9 nM）的选择性是对ADAMTS5（IC50 = 110 nM）的12倍，与EDV33（IC50 = 70 nM）相比，对ADAMTS7的抑制作用增加了8倍。这些取代改变了选择性，产生了一种新的强效ADAMTS7抑制剂，可进一步进行表征。
