Respiratory syncytial virus fusion inhibitors. Part 5: Optimization of benzimidazole substitution patterns towards derivatives with improved activity.
Extensive SAR studies and optimization of ADME properties of benzimidazol-2-one derivatives led to the identification of BMS-433771 (3) as an orally active RSV fusion inhibitor. In order to extend the structure-activity relationships for this compound series, substitution of the benzimidazole ring was examined with a view to establishing additional productive interactions between the inhibitor and functionality present in the proposed binding pocket. Amongst the compounds synthesized, the 5-aminomethyl analogue 10aa demonstrated potent antiviral activity towards wild-type RSV and retained excellent inhibitory activity towards a virus that had been developed to express resistance to BMS-433771 (3), data consistent with an additional productive interaction between the inhibitor and the fusion protein target.
Wang
Xiangdong Alan
XA
Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. xiangdong.wang@bms.com
Cianci
Christopher W
CW
Yu
Kuo-Long
KL
Combrink
Keith D
KD
Thuring
Jan W
JW
Zhang
Yi
Y
Civiello
Rita L
RL
Kadow
Kathleen F
KF
Roach
Julia
J
Li
Zhufang
Z
Langley
David R
DR
Krystal
Mark
M
Meanwell
Nicholas A
NA
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication
D000998:Antiviral Agents; D001562:Benzimidazoles