SIMEPREVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C38H47N5O7S2
Molecular Weight	749.939
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[H][C@@]12C[C@H](C[C@@]1([H])C(=O)N(C)CCCCC=C[C@@H]3C[C@]3(NC2=O)C(=O)NS(=O)(=O)C4CC4)OC5=CC(=NC6=C5C=CC(OC)=C6C)C7=NC(=CS7)C(C)C

InChI

InChIKey=JTZZSQYMACOLNN-VDWJNHBNSA-N

InChI=1S/C38H47N5O7S2/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H,41,44)(H,42,46)/b10-8-/t23-,24-,27-,28-,38-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C38H47N5O7S2
Molecular Weight	749.939
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	5 / 5
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor approved for the treatment of Chronic Hepatitis C (genotype 1 and 4). Inhibiting NS3/4A, simeprevir blocks viral replication. In in vitro assays simeprevir was potent against HCV genotype 1a and 1b. Simeprevir must not be administered as monotherapy and should only be prescribed with both peginterferon alfa and ribavirin.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Q91RS4_9HEPC 2	Inhibitor 8,297		0.36 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic hepatitis C 42	Primary		Approved 8,429	OLYSIO

C_max

Value	Dose	Analyte	Population
11470 ng/mL	200 mg 1 times / day multiple, oral	SIMEPREVIR plasma	Homo sapiens
2304 ng/mL	200 mg single, oral	SIMEPREVIR plasma	Homo sapiens
4067 ng/mL	200 mg single, oral	SIMEPREVIR plasma	Homo sapiens
6172 ng/mL	200 mg 1 times / day multiple, oral	SIMEPREVIR plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
206000 ng × h/mL	200 mg 1 times / day multiple, oral	SIMEPREVIR plasma	Homo sapiens
24630 ng × h/mL	200 mg single, oral	SIMEPREVIR plasma	Homo sapiens
56430 ng × h/mL	200 mg single, oral	SIMEPREVIR plasma	Homo sapiens
79710 ng × h/mL	200 mg 1 times / day multiple, oral	SIMEPREVIR plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
41.32 h	200 mg 1 times / day multiple, oral		SIMEPREVIR plasma	Homo sapiens
16.04 h	200 mg 1 times / day multiple, oral		SIMEPREVIR plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
200 mg 1 times / day multiple, oral	unhealthy, 18–70 years n = 37	Other AEs: Headache, Diarrhoea...
400 mg 1 times / day multiple, oral Highest studied dose	healthy, 24.0 years(range: 20-44 years) n = 9
600 mg single, oral Highest studied dose	healthy, 38.0 years (range: 23-55 years) n = 9
200 mg 2 times / day multiple, oral Highest studied dose	healthy, 38.0 years (range: 25-54 years) n = 9	Other AEs: Photosensitivity reaction, Diarrhea...
150 mg 1 times / day steady, oral Recommended	unhealthy, 49 years (range: 18-73 years) n = 781	Disc. AE: Pruritus, Psoriasis...

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AEs

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AE	Significance	Dose	Population
Diarrhoea	10.8%	200 mg 1 times / day multiple, oral	unhealthy, 18–70 years n = 37
Fatigue	10.8%	200 mg 1 times / day multiple, oral	unhealthy, 18–70 years n = 37
Pruritus	10.8%	200 mg 1 times / day multiple, oral	unhealthy, 18–70 years n = 37
Headache	13.5%	200 mg 1 times / day multiple, oral	unhealthy, 18–70 years n = 37
Anorexia	8.1%	200 mg 1 times / day multiple, oral	unhealthy, 18–70 years n = 37

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inducer 781	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2A6 707 CYP2C8 911 CYP2C19 1,478 CYP3A 214 OATP1B1 788 NTCP 34 P-gp 1,461 MRP2 383 BSEP 402 CYP1A 72 CYP2E1 882	CYP2C8 693 CYP2C19 991 P-gp 1,537 MRP2 205 BCRP 561 OATP1B1/3 11 OATP2B1 104	CYP1A2 701

Drug as perpetrator

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Target	Modality	Activity
CYP2D6 1,891	inhibitor 3,277	moderate [IC50 42.9 uM]
CYP2C8 965	inhibitor 3,277	moderate [IC50 49.1 uM]
CYP2A6 739	inhibitor 3,277	moderate [IC50 59.7 uM]
CYP1A 121	inhibitor 3,277	no
CYP1A2 1,692	inducer 1,573	no

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Drug as victim

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Target	Modality	Activity
BCRP 561	substrate 3,367	yes
CYP2C19 991	substrate 3,367	yes
CYP2C8 693	substrate 3,367	yes
MRP2 205	substrate 3,367	yes
OATP1B1/3 11	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AChemBlock	R16014
AK Scientific	4041AH
AstaTech	33532
Chem Scene	CS-0338
Hangzhou APIChem Technology	AC-27651

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PubMed

Title	Date	PubMed
No data available in table

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose is one 150 mg capsule taken once daily with food. OLYSIO should be administered with both peginterferon alfa and ribavirin. The recommended treatment duration of OLYSIO with peginterferon alfa and ribavirin is 12 weeks, followed by either 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on prior response status.

Route of Administration: Oral

In Vitro Use Guide

The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 nM (7.05 ng/mL) and 19 nM (14.25 ng/mL), respectively.

Substance Class	Chemical
Record UNII	9WS5RD66HZ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SIMEPREVIR

Official Name

English

TMC435

Common Name

English

TMC435350

Code

English

TMC 435350

Code

English

TMC 435

Code

English

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Classification Tree

Code System

Code

Enzyme Inhibitor

NCI_THESAURUS

C783

Antivirals for treatment of HCV infections

WHO-ATC

J05AP05

Protease inhibitors

WHO-ATC

J05AE14

Established Pharmacologic Class

NDF-RT

N0000182639

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Code System

Code

Type

Description

NDF-RT

N0000182638

PRIMARY

HCV NS3/4A Protease Inhibitors [MoA]

FDA UNII

9WS5RD66HZ

PRIMARY

NCI_THESAURUS

C129015

PRIMARY

DRUG BANK

DB06290

PRIMARY

WIKIPEDIA

Simeprevir

PRIMARY

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Related Record

Type

Details


					9WS5RD66HZ

SIMEPREVIR

EXCRETED UNCHANGED

Comments:

Results from the mass balance trial demonstrated that the majority of the simeprevir dose is absorbed, with only 31.0% of dose excreted as unchanged drug in the feces (Trial C103).

Qualification:

FECAL

Amount:

31 % (average)


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> INHIBITOR

Interaction Type:

WEAK

Qualification:

IC50

Amount:

98.4 microgram/mL (average)


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> INHIBITOR

Comments:

Simeprevir inhibited P-gp-dependent transport of paclitaxel in Caco-2 cells with an IC50 value of 64.4 ug/mL (Study NC113).

Qualification:

IC50

Amount:

64.4 microgram/mL (average)


					S36X2B2WOX

HCV NS3-4A SERINE PROTEASE

TARGET -> INHIBITOR

Interaction Type:

INHIBITOR


					AIN96D6SGL

OATP1B1

TRANSPORTER -> SUBSTRATE

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Related Record

Type

Details


					9WS5RD66HZ

SIMEPREVIR

ACTIVE MOIETY

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Name	Property Type	Amount
Tmax	PHARMACOKINETIC	6 hours (average)

Biological Half-life	PHARMACOKINETIC	41 hours (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator