title: Respiratory syncytial virus fusion inhibitors. Part 5: Optimization of benzimidazole substitution patterns towards derivatives with improved activity.
abstract: 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.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. xiangdong.wang@bms.com
authors.forename: Xiangdong Alan
authors.initials: XA
authors.lastname: Wang
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cianci
authors.forename: Kuo-Long
authors.initials: KL
authors.lastname: Yu
authors.forename: Keith D
authors.initials: KD
authors.lastname: Combrink
authors.forename: Jan W
authors.initials: JW
authors.lastname: Thuring
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rita L
authors.initials: RL
authors.lastname: Civiello
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Kadow
authors.forename: Julia
authors.initials: J
authors.lastname: Roach
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Li
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
mesh_terms: 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
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles