Small-molecule inhibitor: thiorphan

Name

History: D,L-Thiorphan was described by Roques et al. (1980) as an inhibitor of neprilysin (then termed "enkaphalinase") with pharmacological activities.
Peptidases inhibited: Thiorphan is a very selective inhibitor of neprilysin. Other peptidases in family M13 such as endothelin-converting enzyme 1 and Drosophila neprilysin-2 are very weakly inhibited (Thomas et al., 2005).
Mechanism: Inhibition is reversible. Thiorphan interacts with the S1" and S2" subsites of neprilysin (K_i = 4.7 nM: Roques et al., 1980). The potencies of the R and S isomers for the inhibition of neprilysin are similar (Mendelsohn et al., 1985). Angiotensin-converting enzyme compound peptidase (XM02-001) is inhibited much more weakly (K_i = 150 nM), and most effectively by the R-compound (Scott et al., 1985). There is very weak inhibition of emdothelin-converting enzyme 1 (M13.002), matrilysin (M10.007: Oneda & Inouye, 2001 ) and thermolysin (M04.001). The crystal structure of thiorphan bound to thermolysin (K_i = 2 micromolar) has been described by Roderick et al. (1989).
Pharmaceutical relevance: Thiorphan potentiates morphine-induced analgesia and attenuates naloxone-precipitated withdrawal symptoms (Roques et al., 1980). However, Zou et al. (2006) find that inhibition of neprilysin by infusion of thiorphan into the hippocampus causes an accumulation of amyloid beta and impairment of learning and memory.
DrugBank: DB01654

CID at PubChem: 4369380
ChEBI: 106816
Structure
Chemical/biochemical name: IUPAC: 2-[[(2S)-2-benzyl-3-sulfanyl-propanoyl]amino]acetic acid; [N-[(S)-2-(mercaptomethyl)-1-oxo-3-phenylpropyl]glycine] [HSCH2CH(CH2C6H5)CONHC-H2COOH] (thiorphan); [[[(R)-1-(mercaptomethyl)-2-phenylethyl] amino]-3-oxopropanoic acid] (retro-thiorphan ); [HSCH2CH(CH2C6H5)NHCOCH2COOH]
Formula weight: 253

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: The early chemical name that was used was DL-3-mercapto-2-benzylpropanoyl)-glycine (Roques et al., 1980). The thiorphan isomer containing a retro-inverso amide bond, retro-thiorphan (Roques et al., 1983) was found to inhibit neprilysin nearly as well as thiorphan (K_i = 2.3 nM) but with complete selectivity against angiotensin-converting enzyme (K_ii> 10 micromolar).