title: An approach to the identification of potent inhibitors of influenza virus fusion using parallel synthesis methodology.
abstract: 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.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. milind.deshpande@bms.com
authors.forename: M S
authors.initials: MS
authors.lastname: Deshpande
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.forename: G
authors.initials: G
authors.lastname: Luo
authors.forename: C
authors.initials: C
authors.lastname: Cianci
authors.forename: S
authors.initials: S
authors.lastname: Danetz
authors.forename: A
authors.initials: A
authors.lastname: Torri
authors.forename: L
authors.initials: L
authors.lastname: Tiley
authors.forename: M
authors.initials: M
authors.lastname: Krystal
authors.forename: K L
authors.initials: KL
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.forename: Q
authors.initials: Q
authors.lastname: Gao
authors.forename: N A
authors.initials: NA
authors.lastname: Meanwell
mesh_terms: 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*
chemical_list: D000588:Amines; D000998:Antiviral Agents; C105257:BMY 27709; C442397:N-((3-hydroxy-1,5,5-trimethylcyclohexyl)methyl)-3-chlorophenylmethanethioamide; D011807:Quinolizines; D013854:Thioamides