title: Antiviral properties of 3-quinolinecarboxamides: a series of novel non-nucleoside antiherpetic agents.
abstract: Novel antiherpetic 3-quinolinecarboxamides were discovered as part of a drug discovery program at Sterling Winthrop Inc. A major goal of this research was to identify novel non-nucleoside agents possessing activity against acyclovir resistant herpes simplex virus. From screening compound libraries in an HSV-2 plaque reduction assay, 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (1) emerged as an attractive lead structure. By modifying the quinoline ring at the 1-, 2-, 3-, 4-, and 7-positions, analogues were identified that have up to 5-fold increased in vitro potency relative to acyclovir. In a single dose mouse model of infection the 1-(4-FC6H4) analogue 17, one of the most potent derivatives in vitro, displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple dose regimen, however, it was 2-fold less potent. Mechanism of action studies indicate that these new compounds interact with a different, as yet undefined, molecular target than acyclovir.
authors.affiliation: Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, PA 19426-0900, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Wentland
authors.forename: R B
authors.initials: RB
authors.lastname: Perni
authors.forename: P H
authors.initials: PH
authors.lastname: Dorff
authors.forename: R P
authors.initials: RP
authors.lastname: Brundage
authors.forename: M J
authors.initials: MJ
authors.lastname: Castaldi
authors.forename: J A
authors.initials: JA
authors.lastname: Carlson
authors.forename: T R
authors.initials: TR
authors.lastname: Bailey
authors.forename: S C
authors.initials: SC
authors.lastname: Aldous
authors.forename: P M
authors.initials: PM
authors.lastname: Carabateas
authors.forename: E R
authors.initials: ER
authors.lastname: Bacon
authors.forename: R K
authors.initials: RK
authors.lastname: Kullnig
authors.forename: D C
authors.initials: DC
authors.lastname: Young
authors.forename: M G
authors.initials: MG
authors.lastname: Woods
authors.forename: S D
authors.initials: SD
authors.lastname: Kingsley
authors.forename: K A
authors.initials: KA
authors.lastname: Ryan
authors.forename: D
authors.initials: D
authors.lastname: Rosi
authors.forename: M L
authors.initials: ML
authors.lastname: Drozd
authors.forename: F J
authors.initials: FJ
authors.lastname: Dutko
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells; D010948:Viral Plaque Assay
chemical_list: C108950:1-fluorophenyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide; D000998:Antiviral Agents; D011804:Quinolines; D000212:Acyclovir