TELAPREVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C36H53N7O6
Molecular Weight	679.8493
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[H][C@@]12CCC[C@]1([H])[C@H](N(C2)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)C3=CN=CC=N3)C4CCCCC4)C(C)(C)C)C(=O)N[C@@H](CCC)C(=O)C(=O)NC5CC5

InChI

InChIKey=BBAWEDCPNXPBQM-GDEBMMAJSA-N

InChI=1S/C36H53N7O6/c1-5-10-25(29(44)34(48)39-23-15-16-23)40-33(47)28-24-14-9-13-22(24)20-43(28)35(49)30(36(2,3)4)42-32(46)27(21-11-7-6-8-12-21)41-31(45)26-19-37-17-18-38-26/h17-19,21-25,27-28,30H,5-16,20H2,1-4H3,(H,39,48)(H,40,47)(H,41,45)(H,42,46)/t22-,24-,25-,27-,28-,30+/m0/s1

HIDE SMILES / InChI

Molecular Formula	C36H53N7O6
Molecular Weight	679.8493
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	6 / 6
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Telaprevir (marketed under the brand names Incivek and Incivo) is a direct-acting antiviralagent against the hepatitis C virus (HCV). It is a hepatitis C virus NS3/4A protease inhibitor indicated for the treatment of genotype 1 chronic hepatitis C (CHC) in adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve or who have been previously treated with interferon-based treatment, including prior null responders, partial responders, and relapsers in combination with peginterferon alfa and ribavirin. Telaprevir is not used as a monotherapy. It is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. It belongs to the chemical class of alpha-ketoamids and binds to NS3/4A in a covalent but reversible manner.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Hepatitis C virus serine protease, NS3/NS4A 13	Inhibitor 8,297		10.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic hepatitis C 42	Curative		Approved 8,429	INCIVEK

C_max

Value	Dose	Analyte	Population
1940 ng/mL	750 mg 3 times / day steady-state, oral	VRT-127394 plasma	Homo sapiens
511 ng/mL	750 mg single, oral	VRT-127394 plasma	Homo sapiens
3090 ng/mL	750 mg 3 times / day steady-state, oral	TELAPREVIR plasma	Homo sapiens
1740.84 ng/mL	750 mg single, oral	TELAPREVIR plasma	Homo sapiens
3232.22 ng/mL	1500 mg single, oral	TELAPREVIR plasma	Homo sapiens
539.79 ng/mL	375 mg single, oral	TELAPREVIR plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
13274.77 ng × h/mL	750 mg 3 times / day steady-state, oral	VRT-127394 plasma	Homo sapiens
5203 ng × h/mL	750 mg single, oral	VRT-127394 plasma	Homo sapiens
19809.27 ng × h/mL	750 mg 3 times / day steady-state, oral	TELAPREVIR plasma	Homo sapiens
11749.1 ng × h/mL	750 mg single, oral	TELAPREVIR plasma	Homo sapiens
24250.23 ng × h/mL	1500 mg single, oral	TELAPREVIR plasma	Homo sapiens
3146.52 ng × h/mL	375 mg single, oral	TELAPREVIR plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
4.77 h	750 mg single, oral	VRT-127394 plasma	Homo sapiens
3.96 h	750 mg single, oral	TELAPREVIR plasma	Homo sapiens
6.49 h	1500 mg single, oral	TELAPREVIR plasma	Homo sapiens
3.23 h	375 mg single, oral	TELAPREVIR plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
32.5%	375 mg single, oral		TELAPREVIR plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
750 mg 3 times / day multiple, oral Recommended	unhealthy, 58 years n = 1	Disc. AE: DRESS syndrome...
1875 mg 3 times / day multiple, oral Highest studied dose	healthy, adult	Other AEs: Nausea, Headache...
750 mg 3 times / day multiple, oral Recommended	unhealthy, adult n = 1797	Disc. AE: Anemia, Skin disorder...

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AEs

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AE	Significance	Dose	Population
DRESS syndrome	1 patient Disc. AE	750 mg 3 times / day multiple, oral Recommended	unhealthy, 58 years n = 1
Decreased appetite		1875 mg 3 times / day multiple, oral Highest studied dose	healthy, adult
Diarrhea		1875 mg 3 times / day multiple, oral Highest studied dose	healthy, adult
Dysgeusia		1875 mg 3 times / day multiple, oral Highest studied dose	healthy, adult
Headache		1875 mg 3 times / day multiple, oral Highest studied dose	healthy, adult

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	substrate 1,037 inhibitor 1,767	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 P-gp 1,461 UGT1A1 204 OATP1B1 788	CYP1A2 1,054 CYP2C19 991 CYP2E1 667 P-gp 1,537	CYP1A 56 CYP2C19 293 CYP3A 129

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP1A 121	inducer 1,573	likely
UGT1A1 254	inhibitor 3,277	no
P-gp 1,650	inhibitor 3,277	no	yes (co-administration study)
CYP2C19 1,553	inducer 1,573	unlikely
CYP3A 298	inducer 1,573	unlikely

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
CYP1A2 1,054	substrate 3,367	no
CYP2C19 991	substrate 3,367	no
CYP2C9 1,037	substrate 3,367	no
CYP2D6 1,217	substrate 3,367	no

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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
ChEBI	CHEBI:68595	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:68595
ChemicalBook	CB41519837	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB41519837
MolPort	MolPort-006-170-103	https://www.molport.com/shop/molecule-link/MolPort-006-170-103
ZINC	ZINC000003992480	http://zinc15.docking.org/substances/ZINC000003992480
eMolecules	36759428	https://www.emolecules.com/cgi-bin/more?vid=36759428

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PubMed

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Title	Date	PubMed
Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics.	2007 Jun 15	17482818
Inhibitors of hepatitis C virus NS3/4A: alpha-ketoamide based macrocyclic inhibitors.	2009 Apr 15	19285390
MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.	2010 Jan	19841155
Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses.	2011 Sep	21699793
Telaprevir for the treatment of hepatitis C.	2012 Mar	22332992

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Patents

Sample Use Guides

In Vivo Use Guide

1125 mg taken twice daily (10-14 hours apart) with food (not low fat). Incivek must be administered with both peginterferon alfa and ribavirin for all patients for 12 weeks, followed by a response-guided regimen of either 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on viral response and prior response status.

Route of Administration: Oral

In Vitro Use Guide

Telaprevir demonstrated excellent antiviral activity both in genotype 1b HCV replicon cells with the IC50 of 354 nM and in human fetal hepatocytes infected with genotype 1a HCV-positive patient sera (IC50 = 280 nM).

Substance Class	Chemical
Record UNII	655M5O3W0U
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TELAPREVIR

Official Name

English

Telaprevir [WHO-DD]

Common Name

English

VRT-111950

Code

English

VX-950

Code

English

TELAPREVIR [JAN]

Common Name

English

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Classification Tree

Code System

Code

Protease inhibitors

WHO-VATC

QJ05AE11

HEPATITIS, CHRONIC

EMA ASSESSMENT REPORTS

INCIVO (AUTHORIZED: HEPATITIS C, CHRONIC)

Established Pharmacologic Class

NDF-RT

N0000182639

Enzyme Inhibitor

NCI_THESAURUS

C783

Antiviral: HCV

LIVERTOX

NBK548138

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Code System

Code

Type

Description

FDA UNII

655M5O3W0U

PRIMARY

HSDB

8125

PRIMARY

USAN

SS-135

PRIMARY

CAS

402957-28-2

PRIMARY

MESH

C486464

PRIMARY

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Related Record

Type

Details


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> SUBSTRATE


					655M5O3W0U

TELAPREVIR

EXCRETED UNCHANGED

Qualification:

FECAL

Amount:

31.8 % (average)


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Comments:

The protein binding is concentration dependent and decreases with increasing telaprevir concentrations at all concentrations of human serum albumin (HSA) and α-1-acid glycoprotein (AAG). In addition, protein binding of telaprevir is affected by the concentration of HSA and AAG.

Interaction Type:

BINDING

Amount:

[59 to 76] % (average)

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Related Record

Type

Details


					ZDU3WB34L8

TELAPREVIR, (.ALPHA.-KETOAMIDE BOND REDUCED)-

METABOLITE INACTIVE -> PARENT


					52YTW6K39W

VRT-127394

METABOLITE LESS ACTIVE -> PARENT

Comments:

Approximately 30-fold less potent than telaprevir.

Interaction Type:

MAJOR

Qualification:

PLASMA


					RH5TAU3X9J

(3S,3AS,6AR)-2-((2S)-2-(((2S)-2-AMINO-2-CYCLOHEXYL-ACETYL)AMINO)-3,3-DIMETHYL-BUTANOYL)-N-((1S)-1-(2-(CYCLOPROPYLAMINO)-2-OXO-ACETYL)BUTYL)-3,3A,4,5,6,6A-HEXAHYDRO-1H-CYCLOPENTA(C)PYRROLE-3-CARBOXAMIDE

METABOLITE -> PARENT


					2WB23298SP

PYRAZINOIC ACID

METABOLITE -> PARENT


					TST2KY7NE6

(3S,3AS,6AR)-2-((2S)-2-(((2S)-2-CYCLOHEXYL-2-(PYRAZINE-2-CARBONYLAMINO)ACETYL)AMINO)-3,3-DIMETHYL-BUTANOYL)-3,3A,4,5,6,6A-HEXAHYDRO-1H-CYCLOPENTA(C)PYRROLE-3-CARBOXAMIDE

METABOLITE -> PARENT

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Related Record

Type

Details


					655M5O3W0U

TELAPREVIR

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Biological Half-life	PHARMACOKINETIC	[9 to 11] hours (average)

Tmax	PHARMACOKINETIC	5 hours (average)	single dose 375 mg (average)

Volume of Distribution	PHARMACOKINETIC	3.6 Liters/Kilogram (average)

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator