Design, synthesis, and SAR of substituted acrylamides as factor Xa inhibitors.
Substituted acrylamides were used as templates that bridge P1 and P4 binding elements, resulting in a series of potent (sub-nanomolar) and selective factor Xa inhibitors. In this template, cis-geometry of P1 and P4 ligands is highly preferred. SAR on the substituting groups, as well as on modification of P1 and P4 moieties is described. Compounds in this series show good in vivo efficacy in animal models.
Song
Yonghong
Y
Millennium Pharmaceuticals, Inc., 256 East Grand Avenue, South San Francisco, CA 94080, USA. yonghong.song@mpi.com
Clizbe
Lane
L
Bhakta
Chhaya
C
Teng
Willy
W
Li
Wenhao
W
Wu
Yanhong
Y
Jia
Zhaozhong Jon
ZJ
Zhang
Penglie
P
Wang
Lingyan
L
Doughan
Brandon
B
Su
Ting
T
Kanter
James
J
Woolfrey
John
J
Wong
Paul
P
Huang
Brian
B
Tran
Katherine
K
Sinha
Uma
U
Park
Gary
G
Reed
Andrea
A
Malinowski
John
J
Hollenbach
Stan
S
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000990:Antithrombin III / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001682:Biological Availability; D004195:Disease Models, Animal; D015195:Drug Design; D065427:Factor Xa Inhibitors; D008024:Ligands; D008958:Models, Molecular; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013698:Templates, Genetic; D013927:Thrombosis / Q000188:drug therapy
D000178:Acrylamides; D065427:Factor Xa Inhibitors; D008024:Ligands; D000990:Antithrombin III