Small-molecule inhibitor: ONO-4817

Name

Peptidases inhibited: Selectively inhibits matrix metallopeptidases of family M10, though with very little effect on matrix metallopeptidase-1 or matrix metallopeptidase-7. The following K_i values have been reported: matrix metallopeptidase-2 (0.73 nM), matrix metallopeptidase-3 (42 nM), matrix metallopeptidase-7 (2500 nM), matrix metallopeptidase-8 (1.1 nM), matrix metallopeptidase-9 (2.1 nM), matrix metallopeptidase-12 (0.45 nM) and matrix metallopeptidase-13 (1.1 nM). An IC₅₀ value of 1600 nM was determined for matrix metallopeptidase-1 (Yamada et al., 2000).
Pharmaceutical relevance: Several potential therapeutic applications have been described (see Literature).

Inhibitor class: This compound contains functionality of the hydroxamate class of metallopeptidase inhibitors. The first full report of hydroxamates as metallopeptidase inhibitors was that of Nishino & Powers (1978). These are reversible inhibitors in which the hydroxamic acid group forms a bidentate complex with the active site zinc. A structure (Holmes & Matthews, 1981) showed both the carbonyl oxygen and the hydroxyl oxygen close to the zinc. Specificity is achieved by fitting of other parts of the molecules to prime-side substrate-binding sites. An excellent early review of the hydroxamates as metallopeptidase inhibitors was that of Powers & Harper (1986) (pp. 244-253).