Respiratory syncytial virus fusion inhibitors. Part 7: structure-activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo.
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.
Sin
Ny
N
Department of Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, United States. ny.sin@bms.com
Venables
Brian L
BL
Combrink
Keith D
KD
Gulgeze
H Belgin
HB
Yu
Kuo-Long
KL
Civiello
Rita L
RL
Thuring
Jan
J
Wang
X Alan
XA
Yang
Zheng
Z
Zadjura
Lisa
L
Marino
Anthony
A
Kadow
Kathleen F
KF
Cianci
Christopher W
CW
Clarke
Junius
J
Genovesi
Eugene V
EV
Medina
Ivette
I
Lamb
Lucinda
L
Krystal
Mark
M
Meanwell
Nicholas A
NA
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
D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles; D010091:Oximes; D007510:Isatin