title: Respiratory syncytial virus fusion inhibitors. Part 7: structure-activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo.
abstract: A series of bezimidazole-isatin oximes were prepared and profiled as inhibitors of respiratory syncytial virus (RSV) replication in cell culture. Structure-activity relationship studies were directed toward optimization of antiviral activity, cell permeability and metabolic stability in human liver micorosomes (HLM). Parallel combinatorial synthetic chemistry was employed to functionalize isatin oximes via O-alkylation which quickly identified a subset of small, lipophilic substituents that established good potency for the series. Further optimization of the isatin oxime derivatives focused on introduction of nitrogen atoms to the isatin phenyl ring to provide a series of aza-isatin oximes with significantly improved PK properties. Several aza-isatin oximes analogs displayed targeted metabolic stability in HLM and permeability across a confluent monolayer of CaCo-2 cells. These studies identified several compounds, including 18i, 18j and 18n that demonstrated antiviral activity in the BALB/c mouse model of RSV infection following oral dosing.
authors: Department of Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, United States. ny.sin@bms.com
authors: Ny
authors: N
authors: Sin
authors: Brian L
authors: BL
authors: Venables
authors: Keith D
authors: KD
authors: Combrink
authors: H Belgin
authors: HB
authors: Gulgeze
authors: Kuo-Long
authors: KL
authors: Yu
authors: Rita L
authors: RL
authors: Civiello
authors: Jan
authors: J
authors: Thuring
authors: X Alan
authors: XA
authors: Wang
authors: Zheng
authors: Z
authors: Yang
authors: Lisa
authors: L
authors: Zadjura
authors: Anthony
authors: A
authors: Marino
authors: Kathleen F
authors: KF
authors: Kadow
authors: Christopher W
authors: CW
authors: Cianci
authors: Junius
authors: J
authors: Clarke
authors: Eugene V
authors: EV
authors: Genovesi
authors: Ivette
authors: I
authors: Medina
authors: Lucinda
authors: L
authors: Lamb
authors: Mark
authors: M
authors: Krystal
authors: Nicholas A
authors: NA
authors: Meanwell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D006801:Humans; D007510:Isatin / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010091:Oximes / Q000737:chemistry*; D051381:Rats; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles; D010091:Oximes; D007510:Isatin