Discovery of Benzoazepinequinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors
| Autor: | Lisha Wang, Hong C. Shen, Zheng Xiufang, Tao Guo, Hongying Yun, Chungen Liang, Lu Gao, Yongfu Liu, Li Chen, Jim Zhen Wu, Song Feng, Baoxia Wang, Lichun Feng |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mutant Administration Oral Biological Availability Pharmacology Oxetane 01 natural sciences Antiviral Agents Virus 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Structure–activity relationship Animals Humans Sulfonyl chemistry.chemical_classification Virtual screening 010405 organic chemistry Quinoline Hep G2 Cells respiratory system Fusion protein 0104 chemical sciences 030104 developmental biology chemistry Respiratory Syncytial Virus Human Quinolines Molecular Medicine Female |
| Zdroj: | Journal of medicinal chemistry. 61(22) |
| ISSN: | 1520-4804 |
| Popis: | A novel benzoazepinequnoline (BAQ) series was discovered as RSV fusion inhibitors. BAQ series originated from compound 2, a hit from similarity-based virtual screening. In SAR exploration, benzoazepine allowed modifications in the head moiety. Benzylic sulfonyl on benzoazepine and 6-Me on quinoline were crucial for good anti-RSV activity. Although the basic amine in the head portion was crucial for anti-RSV activity, the attenuated basicity was required to reduce Vss. Introducing oxetane to the head portion led to discovery of compound 1, which demonstrated single-digit nM anti-RSV activity against different RSV strains, reasonable oral exposure in plasma, and 78-fold higher exposure in lung. Compound 1 also displayed 1 log viral reduction in a female BALB/c mice RSV model by b.i.d. oral dosing at 12.5 mg/kg. A single resistant mutant at L138F in fusion protein proved compound 1 to be a RSV fusion inhibitor. |
| Databáze: | OpenAIRE |
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