Thiorphan

Thiorphan is a selective Neprilysin (NEP) inhibitor with an IC₅₀ value of 6.9nM^[1]. Thiorphan has antidiarrhoeal and neuroprotective effects^[2][3].

The highest non-cytotoxic concentration of Thiorphan (500μM) enhanced the antiproliferative effect of osteosarcoma HOS cells and had a synergistic effect when used in combination with Alpha-ketoglutarate ^[4]. Thiorphan (10µM; 48h) decreased the OGR1-induced inhibition of A549 cell migration^[5].

Thiorphan (50mg/kg) reduced Ibotenate-induced cortical lesions by to 57% and cortical caspase-3 cleavage by to 59%. This neuroprotective effect was long-lasting and was still observed when Thiorphan was administered 12h after the insult^[3]. In a rat model of diabetic cardiomyopathy, the combination of Thiorphan (0.1mg/kg/d; po; 4 weeks) and Telmisartan attenuated inflammatory (NF-jB/MCP-1), profibrotic (TGF-b/Smad7), and apoptotic (PARP/Caspase-3) responses^[6].

References:
[1].Roques B P, Fournie-Zaluski M C, Soroca E, et al. The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice[J]. Nature, 1980, 288(5788): 286-288.
[2]. Stanović S, Boranić M, Petrovecki M, et al. Thiorphan, an inhibitor of neutral endopeptidase/enkephalinase (CD10/CALLA) enhances cell proliferation in bone marrow cultures of patients with acute leukemia in remission[J]. Haematologia, 2000, 30(1): 1-10.
[3].Medja F, Lelievre V, Fontaine R H, et al. Thiorphan, a neutral endopeptidase inhibitor used for diarrhoea, is neuroprotective in newborn mice[J]. Brain, 2006, 129(12): 3209-3223.
[4]. Mizerska-Kowalska M, Sławińska-Brych A, Niedziela E, et al. Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells[J]. Molecules, 2022, 28(1): 97.
[5].Sharma A L, Meitei P M, Machathoibi T C, et al. Ovarian cancer G protein-coupled receptor 1 inhibits A549 cells migration through casein kinase 2α intronless gene and neutral endopeptidase[J]. BMC cancer, 2022, 22(1): 143.
[6]. Malek V, Gaikwad A B. Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy[J]. Cardiovascular Research, 2019, 115(2): 373-384.

Thiorphan是一种选择性脑啡肽（NEP）抑制剂，IC₅₀值为6.9nM^[1]。Thiorphan 具有止泻和神经保护作用^[2][3]。

Thiorphan的最高无细胞毒性浓度（500μM）增强了骨肉瘤HOS细胞的抗增殖作用，与α-酮戊二酸（Alpha-Ketoglutarate）联合使用时具有协同作用^[4]。Thiorphan（10µM；48h）降低了OGR1诱导的A549细胞迁移抑制^[5]。

Thiorphan（50mg/kg）可使伊博替尼（Ibotenate）诱发的皮质损伤减少57%，半胱天冬酶-3（caspase-3）裂解减少59%，这种神经保护作用持久，在损伤后12小时服用仍可观察到^[3]。在糖尿病性心肌病大鼠模型中，Thiorphan（0.1 mg/kg/d；po；4 weeks）和替米沙坦（Telmisartan）的组合可减弱炎症（NF-JB/MCP-1）、促纤维化（TGF-b/Smad7）和凋亡（PARP/Caspase-3）反应^[6]。