Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability.
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.
Yu
Kuo-Long
KL
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
Sin
Ny
N
Civiello
Rita L
RL
Wang
X Alan
XA
Combrink
Keith D
KD
Gulgeze
H Belgin
HB
Venables
Brian L
BL
Wright
J J Kim
JJ
Dalterio
Richard A
RA
Zadjura
Lisa
L
Marino
Anthony
A
Dando
Sandra
S
D'Arienzo
Celia
C
Kadow
Kathleen F
KF
Cianci
Christopher W
CW
Li
Zhufang
Z
Clarke
Junius
J
Genovesi
Eugene V
EV
Medina
Ivette
I
Lamb
Lucinda
L
Colonno
Richard J
RJ
Yang
Zheng
Z
Krystal
Mark
M
Meanwell
Nicholas A
NA
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
D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles