Small-molecule inhibitor: RB 101(S)

Name

History: RB 101 was described as a 'mixed inhibitor-prodrug' to inhibit two peptidases responsible for the degradation of enkaphalins (Fournie-Zaluski et al., 1992).
Peptidases inhibited: Inhibits aminopeptidase N and neprilysin.
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: The compound is a potent inhibitor of enkaphalin degradation, and physiological effects that have been described include analgesia (Noble et al., 1992), antinociceptive effects (Jayaram et al., 1997) and extinction of conditioned fear response (McNally, 2005).

Structure
Chemical/biochemical name: N-[(S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl]-L-phenylalanine benzyl ester

Inhibitor class: This compound is a thiol-containing metallopeptidase inhibitor. In these, an interaction between the thiol group of the inhibitor and zinc in the active site of the enzyme contributes to inhibitory potency. Among the first of such compounds to be described was captopril (Cushman et al., 1977). Reviewed by Powers & Harper (1986), pp. 254 - 263. Thiol-containing metallopeptidase inhibitors include captopril, CGS 35601, GEMSA, omapatrilat, RB 101(S), thiorphan.
Comment: RB 101 has proved to be a valuable tool for investigation of the pharmacology of the enkephalins. Much of the early work with RB 101 was done with the (R,S)-form of the compound, but recent work has used the S-isomer.