Discovery of Piperazinylquinoline Derivatives as Novel Respiratory Syncytial Virus Fusion Inhibitors.
A novel series of piperazinylquinoline derivatives were discovered as respiratory syncytial virus (RSV) fusion inhibitors by the ligand-based screening approach. Among 3,000 hits, 1-amino-3-[[2-(4-phenyl-1-piperidyl)-4-quinolyl]amino]propan-2-ol (7) was proven to be active against the RSV long (A) strain. The anti-RSV activity was improved by converting piperidine to benzylcarbonyl substituted piperazine. The basic side chain was also found to be crucial for anti-RSV activity. The selected analogues, 45 and 50, demonstrated anti-RSV activities up to EC50 = 0.028 μM and 0.033 μM, respectively. A direct anti-RSV effect was confirmed by a plaque reduction assay and a fusion inhibition assay. Both 45 and 50 showed promising DMPK properties with good oral bioavailability, and could potentially lead to novel therapeutic agents targeting the RSV fusion process.
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Xiufang
X
Zheng
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Lisha
L
Wang
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Baoxia
B
Wang
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Kun
K
Miao
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Kunlun
K
Xiang
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Song
S
Feng
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Lu
L
Gao
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Hong C
HC
Shen
Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Hongying
H
Yun
Respiratory syncytial virus (RSV); antiviral; fusion inhibitors; piperazine; quinoline