The characterization of potent novel warfarin analogs.
Racemic sodium warfarin, Coumadin, is widely used in the prevention of thromboembolic disease. The present study was undertaken to characterize three novel classes of warfarin analogs, and to compare them with the warfarin enantiomers. All three classes of compounds inhibit vitamin K epoxide reductase, the enzyme inhibited by racemic warfarin. The alcohol and the ester analogs have reduced protein binding compared with R-(+)-warfarin. The ester and the fluoro-derivatives have similar in vivo anticoagulant activity in the rat to that of S-(-)-warfarin. Thus, it is possible to synthesize novel warfarin analogs that differ from racemic warfarin or its enantiomers in certain selected properties.
Kerr
J S
JS
DuPont Merck Pharmaceutical Company, Wilmington, DE 19880-0400, USA. kerrjs@a1.lldmpc.umc.dupont.com
Li
H Y
HY
Wexler
R S
RS
Robinson
A J
AJ
Robinson
C S
CS
Boswell
G A
GA
Krauthauser
C
C
Harlow
P P
PP
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014812:Vitamin K / Q000097:blood; D014813:Vitamin K Deficiency / Q000139:chemically induced / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases