title: Design and synthesis of benzoic acid derivatives as influenza neuraminidase inhibitors using structure-based drug design.
abstract: A series of 94 benzoic acid derivatives was synthesized and tested for its ability to inhibit influenza neuraminidase. The enzyme-inhibitor complex structure was determined by X-ray crystallographic analysis for compounds which inhibited the enzyme. The most potent compound tested in vitro, 5 (4-acetylamino)-3-guanidinobenzoic acid), had an IC50 = 2.5 x 10(-6) M against N9 neuraminidase. Compound 5 was oriented in the active site of the neuraminidase in a manner that was not predicted from the reported active site binding of GANA (4) with neuraminidase. In a mouse model of influenza, 5 did not protect the mice from weight loss due to the influenza virus when dosed intranasally.
authors.affiliation: BioCryst Pharmaceuticals, Inc., Birmingham, Alabama 35244, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chand
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
authors.forename: S
authors.initials: S
authors.lastname: Bantia
authors.forename: N
authors.initials: N
authors.lastname: Chu
authors.forename: L B
authors.initials: LB
authors.lastname: Cole
authors.forename: P L
authors.initials: PL
authors.lastname: Kotian
authors.forename: W G
authors.initials: WG
authors.lastname: Laver
authors.forename: J A
authors.initials: JA
authors.lastname: Montgomery
authors.forename: V P
authors.initials: VP
authors.lastname: Pathak
authors.forename: S L
authors.initials: SL
authors.lastname: Petty
authors.forename: D P
authors.initials: DP
authors.lastname: Shrout
authors.forename: D A
authors.initials: DA
authors.lastname: Walsh
authors.forename: G M
authors.initials: GM
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D019817:Benzoic Acid; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D019817:Benzoic Acid; D009439:Neuraminidase