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.Starting from the ADAMTS5/ADAMTS7 inhibitor EDV33, a structure-based optimization led to the lead compound 3a, with nanomolar activity against ADAMTS7 and good selectivity over ADAMTS5.