Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor.
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
Zhang
Penglie
P
Millennium Pharmaceuticals, Inc, South San Francisco, CA 94080, USA.
Huang
Wenrong
W
Wang
Lingyan
L
Bao
Liang
L
Jia
Zhaozhong J
ZJ
Bauer
Shawn M
SM
Goldman
Erick A
EA
Probst
Gary D
GD
Song
Yonghong
Y
Su
Ting
T
Fan
Jingmei
J
Wu
Yanhong
Y
Li
Wenhao
W
Woolfrey
John
J
Sinha
Uma
U
Wong
Paul W
PW
Edwards
Susan T
ST
Arfsten
Ann E
AE
Clizbe
Lane A
LA
Kanter
James
J
Pandey
Anjali
A
Park
Gary
G
Hutchaleelaha
Athiwat
A
Lambing
Joseph L
JL
Hollenbach
Stanley J
SJ
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D008252:Macaca fascicularis; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats
D000925:Anticoagulants; D001549:Benzamides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D065427:Factor Xa Inhibitors; C000606913:KCNH2 protein, human; D011725:Pyridines; C543086:betrixaban; D015951:Factor Xa