1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 2: A survey of P4 motifs.
A variety of P4 motifs have been examined to increase the binding affinity and in vitro anticoagulant potency of our biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamide-based fXa inhibitors. Highly potent 2-naphthyl-P1 fXa inhibitors (K(i)< or =2 nM) with improved in vitro anticoagulant activity (2xTG< or =1 microM) and respectable pharmacokinetic properties have been discovered.
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
Lane A
LA
Clizbe
Erick A
EA
Goldman
Uma
U
Sinha
Ann E
AE
Arfsten
Susan T
ST
Edwards
Merlyn
M
Alphonso
Athiwat
A
Hutchaleelaha
Robert M
RM
Scarborough
Bing-Yan
BY
Zhu
D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000990:Antithrombin III / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006801:Humans; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000577:Amides; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D000990:Antithrombin III