Design and evaluation of novel tetracyclic benzofurans as palm site allosteric inhibitors of HCV NS5B polymerase
- Resource Type
- Authors
- Xing Dai; Steven W. Ludmerer; Hong Liu; Fangbiao Li; Linda Brockunier; Anandan Palani; Kung-I Feng; Shuwen He; Ravi P. Nargund; Karen Marcantonio
- Source
- Bioorganicmedicinal chemistry letters. 29(24)
- Subject
- Hepatitis C virus
Clinical Biochemistry
Allosteric regulation
Pharmaceutical Science
Microbial Sensitivity Tests
Pharmacology
Viral Nonstructural Proteins
medicine.disease_cause
01 natural sciences
Biochemistry
Antiviral Agents
chemistry.chemical_compound
Structure-Activity Relationship
Pharmacokinetics
Drug Discovery
medicine
Potency
Molecular Biology
NS5B
Benzofurans
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Organic Chemistry
In vitro
0104 chemical sciences
Bioavailability
Ring size
010404 medicinal & biomolecular chemistry
chemistry
Drug Design
Molecular Medicine
- Language
- ISSN
- 1464-3405
Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.