Wentland M P, Perni R B, Dorff P H, Brundage R P, Castaldi M J, Carlson J A, Bailey T R, Aldous S C, Carabateas P M, Bacon E R, Kullnig R K, Young D C, Woods M G, Kingsley S D, Ryan K A, Rosi D, Drozd M L, Dutko F J
Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, PA 19426-0900, USA.
Drug Des Discov. 1997 May;15(1):25-38.
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.
