title: Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability.
abstract: A series of benzimidazole-based inhibitors of respiratory syncytial virus (RSV) fusion were optimized for antiviral potency, membrane permeability and metabolic stability in human liver microsomes. 1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]methyl]-2H-imidazo[4,5-c]pyridin-2-one (6m, BMS-433771) was identified as a potent RSV inhibitor demonstrating good bioavailability in the mouse, rat, dog and cynomolgus monkey that demonstrated antiviral activity in the BALB/c and cotton rat models of infection following oral administration.
authors.affiliation: Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Kuo-Long
authors.initials: KL
authors.lastname: Yu
authors.forename: Ny
authors.initials: N
authors.lastname: Sin
authors.forename: Rita L
authors.initials: RL
authors.lastname: Civiello
authors.forename: X Alan
authors.initials: XA
authors.lastname: Wang
authors.forename: Keith D
authors.initials: KD
authors.lastname: Combrink
authors.forename: H Belgin
authors.initials: HB
authors.lastname: Gulgeze
authors.forename: Brian L
authors.initials: BL
authors.lastname: Venables
authors.forename: J J Kim
authors.initials: JJ
authors.lastname: Wright
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dalterio
authors.forename: Lisa
authors.initials: L
authors.lastname: Zadjura
authors.forename: Anthony
authors.initials: A
authors.lastname: Marino
authors.forename: Sandra
authors.initials: S
authors.lastname: Dando
authors.forename: Celia
authors.initials: C
authors.lastname: D'Arienzo
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Kadow
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cianci
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Li
authors.forename: Junius
authors.initials: J
authors.lastname: Clarke
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Genovesi
authors.forename: Ivette
authors.initials: I
authors.lastname: Medina
authors.forename: Lucinda
authors.initials: L
authors.lastname: Lamb
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004285:Dogs; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects; D051381:Rats; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects*; D016205:Sigmodontinae; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles