Discovery of a Silicon-Containing Pan-Genotype Hepatitis C Virus NS5A Inhibitor
| Autor: | Gai Kuo, Yuan Cao, Hui Qin, Qin Lu, Deyang Chen, Baomin Liu, Yinsheng Zhang, Liu Xushi, Lu Dandan, Hongjiang Xu, Jia Mei, Hengqiao Shen, Song Wei, Xiaojin Wang, Jie Wang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Silicon Genotype Hepatitis C virus Administration Oral Viral Nonstructural Proteins Pharmacology medicine.disease_cause Antiviral Agents 01 natural sciences Mice Random Allocation 03 medical and health sciences Dogs Pharmacokinetics Drug Resistance Viral Drug Discovery medicine Animals Humans Distribution (pharmacology) Potency NS5A 030304 developmental biology EC50 0303 health sciences Chemistry Rats 0104 chemical sciences 010404 medicinal & biomolecular chemistry Toxicity Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry. 63:5312-5323 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00082 |
| Popis: | We describe a study leading to the discovery of compound 11, a pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with excellent potency, metabolic stability, and pharmacokinetics (PK). Compound 11 incorporating a 4-silapiperidine group was discovered by further optimizing our previous lead with a triethylsilyl moiety. It displayed great potency against genotype 1 subtype a (GT1a), -1b, -2a, -3a, -4a, -5a, and -6a with an EC50 range of 0.33-17 pM and improved potency against the resistance-associated variant GT1a_M28T. Pharmacokinetics (PK) study indicated that compound 11 has reasonable PK exposures with a high liver distribution in preclinical animal species (mouse, rat, and dog). The results of a 14 day repeat-dose toxicity study identified the safety of compound 11. |
| Databáze: | OpenAIRE |
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