Substituted acrylamides as factor Xa inhibitors: improving bioavailability by P1 modification.
To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties.
Millennium Pharmaceuticals, Inc., South San Francisco, CA 94080, USA. yonghong.song@mpi.com
Yonghong
Y
Song
Lane
L
Clizbe
Chhaya
C
Bhakta
Willy
W
Teng
Wenhao
W
Li
Paul
P
Wong
Brian
B
Huang
Uma
U
Sinha
Gary
G
Park
Andrea
A
Reed
Robert M
RM
Scarborough
Bing-Yan
BY
Zhu
D000178:Acrylamides / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D000990:Antithrombin III / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001216:Asparagine / Q000737:chemistry; D001550:Benzamidines / Q000737:chemistry; D001682:Biological Availability; D004285:Dogs; D065427:Factor Xa Inhibitors; D006207:Half-Life; D006846:Hydrocarbons, Halogenated / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014357:Trypsin / Q000187:drug effects
D000178:Acrylamides; D001550:Benzamidines; D065427:Factor Xa Inhibitors; D006846:Hydrocarbons, Halogenated; D007546:Isoquinolines; D001216:Asparagine; D000990:Antithrombin III; D014357:Trypsin; D013917:Thrombin