A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide
| Autor: | Sheng-Ju Hsu, Yen-Chun Lee, Iou-Jiun Kang, Jen-Shin Song, Teng-Kuang Yeh, Yu-Sheng Chao, Ya-Wen Tian, Chung-Chi Lee, Hui-Yun Yang, Jyh-Haur Chern, Andrew Yueh, Tsu-An Hsu |
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| Rok vydání: | 2016 |
| Předmět: |
Pyrrolidines
Stereochemistry medicine.drug_class Administration Oral Biological Availability Carboxamide Hepacivirus Viral Nonstructural Proteins Pharmacology Antiviral Agents Pyrrolidine Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Therapeutic index Oral administration Drug Discovery medicine Animals Structure–activity relationship 030212 general & internal medicine Thiazole Rats Bioavailability Thiazoles chemistry Molecular Medicine 030211 gastroenterology & hepatology Lead compound |
| Zdroj: | Journal of Medicinal Chemistry. 60:228-247 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50 = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50 = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater therapeutic index (CC50/EC50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats. |
| Databáze: | OpenAIRE |
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