Cuffaro, Doretta;
Burkhard, Tina;
Bernardoni, Bianca Laura;
Di Leo, Riccardo;
Zhang, Xiaohan;
Galati, Salvatore;
Tuccinardi, Tiziano;
... Nuti, Elisa; + view all
(2024)
Design, synthesis and biological evaluation of arylsulfonamides as ADAMTS7 inhibitors.
RSC Medicinal Chemistry
, 15
(8)
pp. 2806-2825.
10.1039/d4md00149d.
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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.
| Type: | Article |
|---|---|
| Title: | Design, synthesis and biological evaluation of arylsulfonamides as ADAMTS7 inhibitors |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1039/d4md00149d |
| Publisher version: | http://dx.doi.org/10.1039/d4md00149d |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 3.0 Unported Licence, https://creativecommons.org/licenses/by/3.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10199428 |
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