Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P(1) structure-activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides.
Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability.
Jia
Zhaozhong J
ZJ
Medicinal Chemistry Department, Millennium Pharmaceuticals, Inc., 256 East Grand Ave, South San Francisco, CA 94080, USA. zhaozhong.jia@mpi.com
Wu
Yanhong
Y
Huang
Wenrong
W
Goldman
Erick
E
Zhang
Penglie
P
Woolfrey
John
J
Wong
Paul
P
Huang
Brian
B
Sinha
Uma
U
Park
Gary
G
Reed
Andrea
A
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
D000577:Amides / Q000737:chemistry; D000818:Animals; D015195:Drug Design; D065427:Factor Xa Inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D015842:Serine Proteinase Inhibitors