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Simeprevir sodium

Product NameSimeprevir sodium
CAS1241946-89-3
MFC38H47N5O7S2.x(Na)
MW773.94
EINECS
MOL File1241946-89-3.mol

Chemical Properties

storage temp.	Store at -20°C
solubility	DMSO:30.0(Max Conc. mg/mL);38.86(Max Conc. mM) DMSO:PBS (pH 7.2) (1:2):0.33(Max Conc. mg/mL);0.43(Max Conc. mM) DMF:30.0(Max Conc. mg/mL);38.86(Max Conc. mM)
form	A crystalline solid

Usage And Synthesis

Description

Simeprevir is an orally bioavailable and potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease (K_i = 0.36 nM), a serine protease essential for HCV replication. It inhibits HCV viral replication with an EC₅₀ value of 7.8 nM in Huh7 replicon cells using a luciferase-based assay. Simeprevir is effective against the HCV genotypes 1a and 1b in biochemical assays. In Huh7 replicon cells, it is synergistically effective when used in combination with IFN-α or NM-107 and has an additive effect when used with ribavirin . Formulations containing simeprevir have been used, alone or in combination with pegylated IFN-α and ribavirin, for the treatment of HCV.

Uses

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].

in vivo

Simeprevir (TMC435) has moderate terminal elimination half-life (t_1/2=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
Vd_ss (h)	0.49
AUC_0-24 (μM·h)	5.21	2.79
C_max (μM)		0.73
T_max (h)		3.0
T_1/2 (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 (T_max) of 1 hour and 2 hour for rat and monkey, respectively. Concentration at 24 h after dosing (C_{24 h}) of 0.9 and 2.3 ng/mL for rat and monkey, respectively. AUC_0-24h=1173 and 1409 ng·h/mL for rat and monkey, respectively.

References

[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. DOI:10.1016/j.bmcl.2008.07.088
[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. DOI:10.1128/AAC.01058-08
[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. DOI:10.1128/AAC.01569-16
[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. DOI:10.1021/acscentsci.0c01186

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