Discovery of Benzoazepinequinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors

  • J Med Chem. 2018 Nov 21;61(22):10228-10241. doi: 10.1021/acs.jmedchem.8b01394.
Xiufang Zheng  1 ,  Chungen Liang  1 ,  Lisha Wang  1 ,  Baoxia Wang  1 ,  Yongfu Liu  1 ,  Song Feng  1 ,  Jim Zhen Wu  1 ,  Lu Gao  1 ,  Lichun Feng  1 ,  Li Chen  1 ,  Tao Guo  2 ,  Hong C Shen  1 ,  Hongying Yun  1
Affiliations
  • 1. Roche Pharma Research and Early Development , Roche Innovation Center Shanghai , Building 5, 720 Cailun Road , Shanghai 201203 , China.
  • 2. International Discovery Service Unit, Research Service Division , WuXi AppTec (Shanghai) Co., Ltd. , Lane 31, Yiwei Road , Waigaoqiao, Shanghai 200131 China.
PMID: 30339388 DOI: 10.1021/acs.jmedchem.8b01394
Abstract

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.

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