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.
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.