Ki: 4-140 nM

Thiorphan is a neprilysin inhibitor.

Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones. Neprilysin also degrades the amyloid beta peptide with abnormal misfolding and aggregation, which has been implicated as a cause of Alzheimer"s disease.

In vitro: A previous study assessed the effect of thiorphan or captopril on proliferation of two human tumor cell lines, A549 and HL60. The results showed that captopril could inhibit the proliferation of both A549 and HL60 cells lines but thiorphan had antiproliferative effect only on A549 cells in a dose-dependent manner. However, neither captopril nor thiorphan treatment in combination with interferon alpha or doxorubicin was able to enhance cytotoxic potential of doxorubicin and cytostatic activity of interferon alpha [1].

In vivo: Animal study found that intraperitoneal administration of thiorphan reduced ibotenate-induced cortical lesions by up to 57% and cortical caspase-3 cleavage by up to 59%. Such neuroprotective effect was long-lasting and was still observed when thiorphan was administered 12 h after the insult, suggesting a remarkable window for therapeutic intervention [2].

Clinical trial: The possibility that the intravenous infusion of acetorphan, a prodrug of thiorphan, can inhibit plasma and cerebrospinal fluid (CSF) enkephalinase in man was investigated. A decrease of approximately 65% in enzyme activity was observed in both plasma and CSF. Acetorphan could not induce any significant variation of plasma angiotensin-converting enzyme activity [3].

References:[1] Kowalski J, Belowski D, Wielgus J, Gabryel B, Klin M, Herman ZS.  Effect of captopril and thiorphan on the proliferation of human neoplastic cell lines and their influence on cytostatic activity of interferon alpha or cytotoxic activity of doxorubicin. Arch Immunol Ther Exp (Warsz). 1995;43(1):47-50.[2] Medja F, Lelièvre V, Fontaine RH, Lebas F, Leroux P, Ouimet T, Saria A, Rougeot C, Dournaud P, Gressens P.  Thiorphan, a neutral endopeptidase inhibitor used for diarrhoea, is neuroprotective in newborn mice. Brain. 2006 Dec;129(Pt 12):3209-23. [3] Spillantini, M. ,Gepetti, P.,Fanciullacci, M., et al. In vivo “enkephalinase” inhibition by acetorphan in human plasma and CSF. European Journal of Pharmacology 125(1), 147-150 (1986).