TMC435

Simeprevir (TMC435; TMC435350) sodium is an oral, potent and highly specific hepatitis C virus (HCV) NS3/4A protease inhibitor with a Ki of 0.36 nM. Simeprevir sodium inhibits HCV replication with an EC50 of 7.8 nM. Simeprevir sodium also potently suppresses SARS-CoV-2 replication and synergizes with Remdesivir. Simeprevir sodium inhibits the main protease (Mpro) and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, and also modulates host immune responses[1][4].

Signaling Pathways >> Anti-infection >> HCV

Research Areas >> Infection

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA/RNA Synthesis

Signaling Pathways >> Anti-infection >> SARS-CoV

Signaling Pathways >> Metabolic Enzyme/Protease >> HCV Protease

Ki: 0.36 nM (HCV NS3/4A protease)[1] EC50: 7.8 nM (HCV replication)[1] IC50: 9.6±2.3 μM (SARS-CoV-2 Mpro), 5.5±0.2 μM (SARS-CoV-2 RdRp)[4]

Simeprevir (TMC435) inhibits HCV in a dose-dependent manner in Huh7-Luc cells, with EC50 and EC90 values of 8 nM and 24 nM, respectively[2]. Simeprevir (TMC435) inhibits NS3/4A proteases from HCV genotypes 1 to 6 with IC50s of 1/0.9/7/30/1.5/2.2/1.6 nM for 1a/1b/2b/3a/4/5/6, respectively[3]. Simeprevir inhibits SARS-CoV-2 in Vero E6 cells with an IC50 of 9.6±2.3 μM and 5.5±0.2 μM for Mpro and RdRp, respectively[4].

Simeprevir (TMC435) has moderate terminal elimination half-life (t1/2=1.5 h and 4.1 h for rat (3 mg/kg, p.o.), monkey (3 mg/kg, p.o.))[3]. Simeprevir (TMC435350) exhibits a medium-slow rate of absorption, well distribution with the high concentration observed in the liver, and a low clearance[1]. Pharmacokinetic Parameters of Simeprevir (TMC435350) in male Sprague-Dawley rats[1]. IV (2 mg/kg) PO (10 mg/kg) CL (L/h/kg) 0.505 Vdss (h) 0.49 AUC0-24 (μM·h) 5.21 2.79 Cmax (μM) 0.73 Tmax (h) 3.0 T1/2 (h) 2.8 F (%) 11 Liver/plasma ratio at 6 h 63.5 32 Animal Model: Sprague-Dawley (SD) rats and cynomolgus monkeys[3] Dosage: 3 mg/kg Administration: PO; single dosage Result: Time at which peak concentration (Tmax) of 1 hour and 2 hour for rat and monkey, respectively. Concentration at 24 h after dosing (C24 h) of 0.9 and 2.3 ng/mL for rat and monkey, respectively. AUC0-24h=1173 and 1409 ng·h/mL for rat and monkey, respectively.

[1]. Raboisson P, et al. Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8.

[2]. Lin TI, et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.Antimicrob Agents Chemother. 2009 Apr;53(4):1377-85. Epub 2009 Jan 26.

[3]. Rajagopalan R, et al. Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease. Antimicrob Agents Chemother. 2016 Dec 27;61(1). pii: e01569-16.

[4]. Lo HS, et al. Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir. ACS Cent Sci. 2021 May 26;7(5):792-802.