TMC-647055

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C32H38N4O6S
Molecular Weight	606.732
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC2=C(C=C1)C3=C(C4CCCCC4)C5=C6C=C(C=C5)C(=O)NS(=O)(=O)N(C)CCOCCN(C)C(=O)C(CN36)=C2

InChI

InChIKey=UOBYJVFBFSLCTQ-UHFFFAOYSA-N

InChI=1S/C32H38N4O6S/c1-34-13-15-42-16-14-35(2)43(39,40)33-31(37)22-9-11-27-28(19-22)36-20-24(32(34)38)17-23-18-25(41-3)10-12-26(23)30(36)29(27)21-7-5-4-6-8-21/h9-12,17-19,21H,4-8,13-16,20H2,1-3H3,(H,33,37)

HIDE SMILES / InChI

Molecular Formula	C32H38N4O6S
Molecular Weight	606.732
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://adisinsight.springer.com/drugs/800033015
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/22710121

TMC647055 is a potent and selective nonnucleoside inhibitor of NS5B binding site 1 (NNI-1) with activity against most HCV genotypes. Binding of inhibitors to NNI-1 is purported to displace the flexible λ1 loop from its thumb domain binding site, perturbing the interaction between the NS5B polymerase finger and thumb domains and thereby locking the enzyme in an open inactive conformation. Janssen R&D Ireland (formerly Tibotec Pharmaceuticals) is developing TMC 647055 as an oral once-daily treatment for chronic hepatitis C virus infections. Phase II development is underway in Belgium, Germany and the US.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Hepatitis C virus NS5B RNA-dependent RNA polymerase 14 Target ID: CHEMBL5375 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22710121	Inhibitor 8297		4.1 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hepatitis C 42 Sources: http://adisinsight.springer.com/drugs/800033015	Primary		Phase II 1132	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYPs 22	HLM 31 P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYPs 28	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22633687/	no
CYP3A4 1925	inducer 1573 Sources: https://pubs.acs.org/doi/abs/10.1021/jm401396p	yes		yes (expression study) Comment: The plasma concentrations of 4-β-hydroxycholesterol, the endogenous biomarker for CYP3A4 induction, increased with increasing TMC647055 dose in healthy volunteers. Sources: https://pubs.acs.org/doi/abs/10.1021/jm401396p

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363681132	no
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22633687/	yes

PubMed

Title	Date	PubMed
Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055.	2012 Jul 1	22633687
Structure-based macrocyclization yields hepatitis C virus NS5B inhibitors with improved binding affinities and pharmacokinetic properties.	2012 May 7	22473861
TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage.	2012 Sep	22710121
Discovery and early development of TMC647055, a non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase.	2014 Mar 13	24144360
Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055.	2016 Apr	26836778

Patents

Sample Use Guides

In Vivo Use Guide

A phase I trial assessed the safety and tolerability of TMC 647055 administered as an oral solution for 6 days in increasing single doses from 100 mg to 3000 mg in fed conditions and in multiple oral doses (NCT01202825)

Route of Administration: Oral

In Vitro Use Guide

The frequency of resistant colony formation was determined in a colony formation assay using wild-type HCV genotype 1b replicon (Huh7-Luc) cells incubated in the presence of different concentrations of TMC647055, no resistant replicon cell colonies were observed with 1.5 μM TMC647055 alone, indicating complete clearance of the replicon from the cells.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 02:20:14 UTC 2023` Edited by `admin` on `Sat Dec 16 02:20:14 UTC 2023`
Record UNII	11BD024G7J
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TMC-647055

Common Name

English

2,19-METHANO-3,7:4,1-DIMETHENO-1H,11H-14,10,2,9,11,17-BENZOXATHIATETRAAZACYCLODOCOSINE-8,18(9H,15H)-DIONE, 27-CYCLOHEXYL-12,13,16,17-TETRAHYDRO-22-METHOXY-11,17-DIMETHYL-, 10,10-DIOXIDE

Common Name

English

TMC647055

Code

English

Code System Code Type Description

CAS

1204416-97-6