Small-molecule inhibitor: galardin

Name

History: Galardin, under the name GM6001, was one of a series of inhibitors described by Grobelny et al. (1992.
Peptidases inhibited: Matrix metallopeptidase-1 (K_i = 0.4 nM), thermolysin (K_i = 20 nM), pseudolysin (K_i = 20 nM) (Grobelny et al., 1992). Matrix metallopeptidase-3 (Parker et al., 1999). Membrane-type matrix metallopeptidase-1 (Yamamoto et al., 1998). Human meprin A complex peptidase (Kruse et al., 2004). Anthrax lethal factor (Kocer et al., 2005). Adam peptidases (family M12: ), notably those responsible for shedding reactions (Kim et al., 2005). Peptide deformylase (Balakrishnan et al., 2006).
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Inhibitors of matrix metallopeptidases are potentially of pharmaceutical interest. Galardin has been useful in many experimental studies, but is probably too unselective for clinical use.

CID at PubChem: 132519
Structure
Chemical/biochemical name: (2R)-N'-hydroxy-N-[(1S)-2-(1H-indol-3-yl)-1-(methylcarbamoyl)ethyl]-2-(2-methylpropyl)butanediamide
Formula weight: 388

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).
Comment: Also described as N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-L-tryptophane methylamide. Galardin itself has broad specificity for inhibition of metallopeptidases, but related compounds can be more selective (see e.g. Auge et al., 2003).