1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 3: Design, synthesis and SAR of orally bioavailable benzamidine-P4 inhibitors.
Using N,N-dialkylated benzamidines as the novel P4 motifs, we have designed and synthesized a class of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent and selective fXa inhibitors with significantly improved hydrophilicity and in vitro anticoagulant activity. These benzamidine-P4 fXa inhibitors have displayed excellent oral bioavailability and long half-life.
Millennium Pharmaceuticals Inc., 256 East Grand Avenue, South San Francisco, CA 94080, USA. zjia@portola.com
Zhaozhong J
ZJ
Jia
Yanhong
Y
Wu
Wenrong
W
Huang
Penglie
P
Zhang
Yonghong
Y
Song
John
J
Woolfrey
Uma
U
Sinha
Ann E
AE
Arfsten
Susan T
ST
Edwards
Athiwat
A
Hutchaleelaha
Stanley J
SJ
Hollennbach
Joseph L
JL
Lambing
Robert M
RM
Scarborough
Bing-Yan
BY
Zhu
D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D000990:Antithrombin III / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D001550:Benzamidines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001682:Biological Availability; D015195:Drug Design; D006801:Humans; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000577:Amides; D001550:Benzamidines; D011720:Pyrazoles; C031280:pyrazole; D000990:Antithrombin III