A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus
| Autor: | Teng-Kuang Yeh, Jyh-Haur Chern, Andrew Yueh, Chung-Chi Lee, Sheng-Ju Hsu, Chiung-Tong Chen, Yu-Sheng Chao, Hui-Yun Yang, Yen-Chun Lee, Tsu-An Hsu, Ya-Wen Tian, Iou-Jiun Kang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Daclatasvir
Hepatitis C virus Biological Availability Hepacivirus Pharmacology Viral Nonstructural Proteins medicine.disease_cause 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Dogs Pharmacokinetics Oral administration Drug Discovery medicine Potency Animals Humans Thiazole 030304 developmental biology EC50 0303 health sciences 010405 organic chemistry Organic Chemistry General Medicine Amides Hepatitis C Sialyltransferases 0104 chemical sciences Bioavailability Rats Thiazoles chemistry lipids (amino acids peptides and proteins) medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 167 |
| ISSN: | 1768-3254 |
| Popis: | A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1′R,2′S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC50 = 0.003 nM) than daclatasvir (GT1b EC50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC50 > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection. |
| Databáze: | OpenAIRE |
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