Design and synthesis of factor Xa inhibitors and their prodrugs.
In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.
Song
Yonghong
Y
Department of Medicinal Chemistry, Millennium Pharmaceuticals, Inc., 256 East Grand Ave., South, San Francisco, CA 94080, USA. song@mpi.com
Clizbe
Lane
L
Bhakta
Chhaya
C
Teng
Willy
W
Wong
Paul
P
Huang
Brian
B
Tran
Katherine
K
Sinha
Uma
U
Park
Gary
G
Reed
Andrea
A
Scarborough
Robert M
RM
Zhu
Bing Yan
BY
D000578:Amidines / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D065427:Factor Xa Inhibitors; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000578:Amidines; D065427:Factor Xa Inhibitors; D011355:Prodrugs; D015842:Serine Proteinase Inhibitors