An approach to the identification of potent inhibitors of influenza virus fusion using parallel synthesis methodology.
Structure-activity studies associated with the salicylic acid-derived inhibitor of influenza fusion, BMY-27709, were examined using a parallel synthesis approach. This SAR survey led to the discovery of potent influenza inhibitory activity in a series of aromatic amides and thioamides derived from 1,3,3-trimethyl-5-hydroxycyclohexylmethylamine. Select compounds were characterized as inhibitors of the H1 subtype of influenza A viruses that act by preventing the pH-induced fusion process, thereby blocking viral entry into host cells. In a plaque-reduction assay, the most potent inhibitors displayed EC(50) values of 0.02-0.14 microg/mL.
Deshpande
M S
MS
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. milind.deshpande@bms.com
Wei
J
J
Luo
G
G
Cianci
C
C
Danetz
S
S
Torri
A
A
Tiley
L
L
Krystal
M
M
Yu
K L
KL
Huang
S
S
Gao
Q
Q
Meanwell
N A
NA
D000588:Amines / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured / Q000821:virology; D004353:Drug Evaluation, Preclinical; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000472:pathogenicity; D009682:Magnetic Resonance Spectroscopy; D008561:Membrane Fusion / Q000187:drug effects; D015394:Molecular Structure; D011807:Quinolizines / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000737:chemistry* / Q000494:pharmacology*
D000588:Amines; D000998:Antiviral Agents; C105257:BMY 27709; C442397:N-((3-hydroxy-1,5,5-trimethylcyclohexyl)methyl)-3-chlorophenylmethanethioamide; D011807:Quinolizines; D013854:Thioamides