Official websites use. Share sensitive information only on official, secure websites. The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury.
Initially our inhibitors suffered from low selectivity vs MMP Further optimization composed of employing 5-membered heteroaromatic groups as hydantoin substituents to become more potent on ADAMTS7.
Further optimization to improve selectivity vs ADAMTS12 seems possible, and a respective starting point could be identified. Atherosclerosis remains a leading cause of death worldwide 1 despite widespread statin use and more recent advances like PCSK9 targeting.
Among those targets is ADAMTS7 a disintegrin and metalloproteinase with thrombospondin type 1 repeats 7 6 with the leading single nucleotide polymorphism SNP rs 7 , 8 resulting in a serine to proline switch in the prodomain of the enzyme. The wild-type serine containing ADAMTS7 could be related to higher cardiovascular CV mortality 9 and other secondary CV events 10 , 11 compared to the low-frequency mutant proline variant. This hypothesis was further substantiated when it was found that knockout of ADAMTS7 reduced atherosclerosis in mice with a hyperlipidemic phenotype and neointima proliferation as compared to wild-type controls.
ADAMTS7 belongs to a family of 19 secreted zinc metalloproteases 27 , 28 with proteolytic activity against extracellular substrates 15 , 29 , 30 including matrix proteins.
