8RIJ

Discovery of the first orally bioavailable ADAMTS7 inhibitor BAY-9835

This is a non-PDB format compatible entry.

Summary for 8RIJ

• Entry DOI: 10.2210/pdb8rij/pdb
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: matrix metalloproteinase, mmp12, metallo elastase, extracellular matrix, hydrolase, metal-binding, metalloprotease
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18235.43

Authors

Schafer, M.,Meibom, D.,Wasnaire, P.,Beyer, K.,Broehl, A.,Cancho-Grande, Y.,Elowe, N.,Henninger, K.,Johannes, S.,Jungmann, N.,Krainz, T.,Lindner, N.,Maassen, S.,MacDonald, B.,Menshykau, D.,Mittendorf, J.,Sanchez, G.,Stefan, E.,Torge, A.,Xing, Y.,Zubov, D. (deposition date: 2023-12-18, release date: 2024-02-21, Last modification date: 2024-03-06)

Primary citation

Meibom, D.,Wasnaire, P.,Beyer, K.,Broehl, A.,Cancho-Grande, Y.,Elowe, N.,Henninger, K.,Johannes, S.,Jungmann, N.,Krainz, T.,Lindner, N.,Maassen, S.,MacDonald, B.,Menshykau, D.,Mittendorf, J.,Sanchez, G.,Schaefer, M.,Stefan, E.,Torge, A.,Xing, Y.,Zubov, D.
BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.
J.Med.Chem., 67:2907-2940, 2024

PubMed Abstract: 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.

PubMed: 38348661
DOI: 10.1021/acs.jmedchem.3c02036

Experimental method

X-RAY DIFFRACTION (1.96 Å)