3-QUINOLINECARBOXAMIDES - A SERIES OF NOVEL ORALLY-ACTIVE ANTIHERPETIC AGENTS

A series of novel 3-quinolinecarboxamides that are structurally simila r to the quinolone class of antibacterial agents possess excellent ant iherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3 -, and 7-positions, analogues were identified that have up to 5-fold i ncreased HSV-2 plaque-reduction potency relative to acyclovir. In a si ngle-dose mouse model of infection, one of the most potent derivatives in vitro, hydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (97), di splayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple-dose regimen, however, 97 was 2-fold less potent. In mice dosed orally with 97, sustained plasma drug levels were evide nt that may account for the high efficacy observed. The molecular mech anism of action of these agents is not known; however, based on in vit ro studies with acyclovir resistant mutants, it is likely that the mec hanism differs from that of acyclovir. In vitro plaque-reduction poten cy was not generally predictive of oral efficacy in mice. An X-ray cry stal structure of 97 corroborated the assignment of structure and prov ided useful insights as to the effect of conformation on plaque-reduct ion potency.