Targeting ADAMTS-7: A Vaccination Against Atherosclerosis—and Its Complications?

Kessler, Thorsten; Schunkert, Heribert

doi:10.1161/circulationaha.122.063495

Cited by 1 publication

(3 citation statements)

References 16 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consequently, ADAMTS7 antibodies raised against the ADAMTS7 catalytic domain protected against stent-induced restenosis in a preclinical swine model. 24,25 Furthermore, high ADAMTS7 levels were identified in heart tissue 20 and injured vessels, 18 which is in line with the CAD protection conferred by the low risk allele and the intimal thickening induced by the high risk allele as detailed above. Collectively, the data suggest that ADAMTS7 inhibition might be a new way to treat CAD and restenosis.…”

Section: ■ Introductionsupporting

confidence: 65%

“…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. , According to a recent study, loss of the catalytic function of ADAMTS7 protects against atherogenesis via a phenotypic switch of VSMCs, suggesting that the catalytic domain should be an attractive target for therapeutic intervention , to treat coronary artery disease as well as conditions associated with intima hyperplasia. Consequently, ADAMTS7 antibodies raised against the ADAMTS7 catalytic domain protected against stent-induced restenosis in a preclinical swine model. , Furthermore, high ADAMTS7 levels were identified in heart tissue and injured vessels, which is in line with the CAD protection conferred by the low risk allele and the intimal thickening induced by the high risk allele as detailed above. Collectively, the data suggest that ADAMTS7 inhibition might be a new way to treat CAD and restenosis …”

Section: Introductionmentioning

confidence: 52%

“…LC−MS (Method 2): Rt = 1. Ent (25). Enantiomeric separation of 500 mg of rac-N-{[4-(1-ethyl-1H-pyrazol-5-yl)-2,5-dioxoimidazolidin-4-yl]methyl}-4′-(trifluoromethyl)[biphenyl]-2carboxamide was done using the following preparative chiral HPLC method: Machine: ABSYS SFC; Column: Chiralpak AD-H 5 μm, 250 × 25 mm 2 ; Eluent: CO 2 /Methanol 80%: 20%; Flow: 140 mL/min; Backpressure: 100 bar; UV-detection: 210 nm.…”

Section: Imidazolidin-4-yl]methyl}-4′-(trifluoromethyl)[biphenyl]-2-c...mentioning

confidence: 99%

See 2 more Smart Citations

BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor

Meibom,

Wasnaire,

Beyer

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

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. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign. Initially our inhibitors suffered from low selectivity vs MMP12. An X-ray cocrystal structure inspired us to exploit amino acid differences in the binding site of MMP12 and ADAMTS7 to improve selectivity. Further optimization composed of employing 5-membered heteroaromatic groups as hydantoin substituents to become more potent on ADAMTS7. Finally, fine-tuning of DMPK properties yielded BAY-9835, the first orally bioavailable ADAMTS7 inhibitor. Further optimization to improve selectivity vs ADAMTS12 seems possible, and a respective starting point could be identified.

show abstract