Antiviral properties of 3-quinolinecarboxamides: a series of novel non-nucleoside antiherpetic agents.
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.
Wentland
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Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, PA 19426-0900, USA.
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Dorff
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Castaldi
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Carlson
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Bailey
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Carabateas
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Kingsley
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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
C108950:1-fluorophenyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide; D000998:Antiviral Agents; D011804:Quinolines; D000212:Acyclovir