Design, synthesis and biological evaluation of arylsulfonamides as ADAMTS7 inhibitors.
RSC Med Chem
; 15(8): 2806-2825, 2024 Aug 14.
Article
em En
| MEDLINE
| ID: mdl-39149096
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 (K i = 9 nM) over ADAMTS5 (K i = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 (K i = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article