General
Preferred name
SIMEPREVIR
Synonyms
TMC435 ()
TMC-435350 ()
SIMEPREVIR SODIUM ()
Simeprevir (TMC435) ()
TMC435350 ()
TMC 435350 ()
TMC 435 ()
Olysio ()
TMC-435 ()
Simeprevir (sodium salt) ()
P&D ID
PD039117
CAS
923604-59-5
1241946-89-3
Tags
natural product
drug
available
Approved by
EMA
FDA
First approval
2013
Drug Status
approved
Drug indication
Chronic HCV-1 infection
Max Phase
Phase 4
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA
Simeprevir is accumulated in the liver after uptake into hepatocytes via OATP1B1/3. NS3/4A heterodimeric complex is composed of the cofactor N4A subunit and N3 subunit which contains the proteolytic site. The NS3/4A protease cleaves the HCV polyprotein downstream of the NS3 site, generating non-structural viral proteins NS3, NS4A, NS4B, NS5A and NS5A and subsequently formation of mature proteins [A19630, A19632]. Simeprevir exerts an inhibitory action on HCV polyprotein cleavage via induced-fit binding to an extended S2 subsite located in the NS3 catalytic site [A19633]. NS3/4A inhibitors usually depend on few interactions located in the substrate binding groove of the viral serine protease, thus are susceptible to resistance and failed treatment from few critical mutations in these sites. ; At higher concentration above their antiviral half-maximal effective concentration (EC50), simeprevir and other NS3/4A inhibitors also restore interferon (IFN)-signaling pathways that are thought to be disrupted by NS3/4A protease and recover innate immune processes. NS3/4A protease cleaves two essential adaptor proteins that initiate signaling leading to activation of IFN regulatory factor 3 and IFN-α/β synthesis, which are mitochondrial antiviral-signaling proteins (MAVS otherwise known as IPS-1, VISA, or Cardif) and toll/interleukin-1 receptor (TIR)- domain-containing adaptor-inducing IFN-β (TRIF). Blocking the function of these adaptor proteins results in impaired interferon induction. NS3/4A inhibitors recover the proper IFN-signaling pathways [A19630, A19632].
DESCRIPTION
Simeprevir is a hepatitis C virus NS3/4A protease inhibitor.
(GtoPdb)
INDICATION
Indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection: typically in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis and in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis. ; ; Resistance: Reduced susceptibility to simeprevir was most commonly associated with the viral NS3 Q80K polymorphism. Amino acid substitutions at NS3 positions S122, R155 and/or D168 are also shown to reduce susceptibility to simeprevir in genotype 1a/b patients. ;
ABSORPTION
The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir capsule in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically; achieved between 4 to 6 hours following the oral administration.
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
0
Organisms
1
Compound Sets
15
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
Guide to Pharmacology
LSP-MoA library (Laboratory of Systems Pharmacology)
ReFrame library
Selleckchem Bioactive Compound Library
TargetMol Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
40
Molecular Weight
749.29
Hydrogen Bond Acceptors
10
Hydrogen Bond Donors
2
Rotatable Bonds
8
Ring Count
7
Aromatic Ring Count
3
cLogP
5.25
TPSA
156.89
Fraction CSP3
0.55
Chiral centers
5.0
Largest ring
14.0
QED
0.29
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
Microbiology&virology
Target
HCV NS3/4A protease
HCV
CYP1A2, CYP3A4
MOA
HCV Protease
HCV inhibitor
Indication
hepatitis C
Therapeutic Class
Antiinfective Agents
Source data
