Small-molecule inhibitor: CGS27023A

Name

History: The design, synthesis and properties of CGS27023A were described by MacPherson et al. (1997).
Peptidases inhibited: Matrix metallopeptidases (family M10) are inhibited. K_i values for matrix metallopeptidases have been reported for matrix metallopeptidase-9 (8 nM), matrix metallopeptidase-2 (20 nM), matrix metallopeptidase-1 (33 nM) and matrix metallopeptidase-3 (43 nM) (MacPherson et al., 1997). There is also inhibition of MMP12 and MMP-13 (Moy et al., 2000; Nar et al., 2001).
Mechanism: Inhibition is tight-binding, reversible.
Pharmaceutical relevance: CGS27023A has been found to inhibit the degradation of cartilage extracellular matrix in experimental models (Ganu et al., 1999). The compound has also been described as as an anti-tumor angiogenic drug (Nakamura et al., 2003), and shown to exert a protective effect against epidermal basement membrane damage (Amano et al., 2005).

Structure
Chemical/biochemical name: N-hydroxy-2(R)-[(4-methoxysulfonyl)-(3-picolyl)-amino]-3-methylbutanamide hydrochloride monohydrate

Synthesis: The synthesis was initially described by MacPherson et al. (1997), but subsequent reports have described radiolabeled and (18)F-labelled derivatives (see Literature). CGS27023A was an early example of the class of sulfonamide-containing hydroxamate inhibitors, and the role of the sulfonamide in these has been reviewed by Cheng et al. (2008).

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).