Discovery of ASP5286: A novel non-immunosuppressive cyclophilin inhibitor for the treatment of HCV
| Autor: | David A. Barrett, Seiji Yoshimura, Masae Sawada, Toshio Yamanaka, Takuya Makino, Eisaku Tsujii, Masahiro Neya |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Hepatitis C virus
Clinical Biochemistry Pharmaceutical Science Hepacivirus Microbial Sensitivity Tests Pharmacology medicine.disease_cause 01 natural sciences Biochemistry Antiviral Agents Cyclophilins Structure-Activity Relationship Pharmacokinetics Cyclosporin a Aqueous solubility Drug Discovery medicine Potency Molecular Biology Cyclophilin Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry virus diseases 0104 chemical sciences 010404 medicinal & biomolecular chemistry Molecular Medicine Immunosuppressive Agents |
| Zdroj: | Bioorganicmedicinal chemistry letters. 30(16) |
| ISSN: | 1464-3405 |
| Popis: | Evidence indicates that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in its replication, and cyclophilin inhibitors represent a new class of anti-HCV agents. We have established an efficient synthetic methodology to generate FR901459 derivatives via N, O-acyl migration reaction while avoiding total synthesis. Through a detailed structure-activity relationship study, we improved anti-HCV activity while decreasing immunosuppressive activity. Additionally, we discovered the importance of substitution at the 3 position for not only improving anti-HCV activity but also pharmacokinetic profile. Finally, by striking an appropriate balance between potency, solubility, and permeability, we discovered ASP5286 (13) as a potential clinical candidate for anti-HCV therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect