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Antimicrobial Agents and Chemotherapy, February 2004, p. 413-422, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.413-422.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Orally Active Fusion Inhibitor of Respiratory Syncytial Virus

Christopher Cianci, Kuo-Long Yu, Keith Combrink, Ny Sin, Bradley Pearce, Alan Wang, Rita Civiello, Stacey Voss, Guangxiang Luo, Kathy Kadow, Eugene V. Genovesi, Brian Venables, Hatice Gulgeze, Ashok Trehan, Jennifer James, Lucinda Lamb, Ivette Medina, Julia Roach, Zheng Yang, Lisa Zadjura, Richard Colonno, Junius Clark, Nicholas Meanwell, and Mark Krystal^*

The Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492

Received 7 July 2003/ Returned for modification 9 October 2003/ Accepted 4 November 2003

BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.

Present address: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285-0438.

Present address: Cumbre, Inc., Dallas, TX 75235.

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