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Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Nov 15; Vol. 25 (22), pp. 5427-36. Date of Electronic Publication: 2015 Sep 05. - Publication Year :
- 2015
-
Abstract
- Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Haplorhini
Hepatocytes enzymology
Humans
Inhibitory Concentration 50
Mice
Microsomes, Liver enzymology
Molecular Structure
Rats
Rats, Sprague-Dawley
Serine Proteinase Inhibitors chemical synthesis
Serine Proteinase Inhibitors chemistry
Serine Proteinase Inhibitors pharmacology
Viral Nonstructural Proteins chemistry
Drug Discovery
Hepacivirus drug effects
Macrocyclic Compounds chemistry
Macrocyclic Compounds pharmacology
Viral Nonstructural Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26410074
- Full Text :
- https://doi.org/10.1016/j.bmcl.2015.09.009