3-Quinolinecarboxamides. A series of novel orally-active antiherpetic agents.
A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency relative to acyclovir. In a single-dose mouse model of infection, one of the most potent derivatives in vitro, 1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarbo xamide (97), displayed 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 evident that may account for the high efficacy observed. The molecular mechanism of action of these agents is not known; however, based on in vitro studies with acyclovir resistant mutants, it is likely that the mechanism differs from that of acyclovir. In vitro plaque-reduction potency was not generally predictive of oral efficacy in mice. An X-ray crystal structure of 97 corroborated the assignment of structure and provided useful insights as to the effect of conformation on plaque-reduction potency.
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, Pennsylvania 19426-0900.
M P
MP
Wentland
R B
RB
Perni
P H
PH
Dorff
R P
RP
Brundage
M J
MJ
Castaldi
T R
TR
Bailey
P M
PM
Carabateas
E R
ER
Bacon
D C
DC
Young
M G
MG
Woods
D000212:Acyclovir / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004352:Drug Resistance, Microbial; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy; D051379:Mice; D008813:Mice, Inbred ICR; D011804:Quinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014709:Vero Cells; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D011804:Quinolines; D000212:Acyclovir