Small-molecule inhibitor: TAPI

Name

History: TAPI was first described by Mohler et al. (1994) (their compound 2) as a potent inhibitor of tumour necrosis factor processing that protected mice from a lethal dose of endotoxin.
Peptidases inhibited: Inhibits adam 17 peptidase. Human meprin is also inhibited (Kruse &etal, 2004).

CID at PubChem: 3035404
Structure
Chemical/biochemical name: N-{D,L-[2-(hydroxyaminocarbonyl)-methyl]-4-methylpentanoyl}L-3-(2' naphthyl)-alanyl-L-alanine amide
Formula weight: 457

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).