Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors.
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Ye
Bin
B
Berlex Biosciences, Post Office Box 4099, Richmond, California 94804-0099, USA. rickbinye@yahoo.com
Arnaiz
Damian O
DO
Chou
Yuo-Ling
YL
Griedel
Brian D
BD
Karanjawala
Rushad
R
Lee
Wheeseong
W
Morrissey
Michael M
MM
Sacchi
Karna L
KL
Sakata
Steven T
ST
Shaw
Kenneth J
KJ
Wu
Shung C
SC
Zhao
Zuchun
Z
Adler
Marc
M
Cheeseman
Sarah
S
Dole
William P
WP
Ewing
Janice
J
Fitch
Richard
R
Lentz
Dao
D
Liang
Amy
A
Light
David
D
Morser
John
J
Post
Joseph
J
Rumennik
Galina
G
Subramanyam
Babu
B
Sullivan
Mark E
ME
Vergona
Ron
R
Walters
Janette
J
Wang
Yi-Xin
YX
White
Kathy A
KA
Whitlow
Marc
M
Kochanny
Monica J
MJ
D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D011517:Prothrombin Time; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020246:Venous Thrombosis / Q000188:drug therapy; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
C531037:3-chloro-N-(4-chloro-2-(((5-chloro-2-pyridinyl)amino)carbonyl)-6-methoxyphenyl)-4-(((4,5-dihydro-2-oxazolyl)methylamino)methyl)-2-thiophenecarboxamide; C531036:3-chloro-N-(4-chloro-2-(((5-chloro-2-pyridinyl)amino)carbonyl)-6-methoxyphenyl)-4-((methylamino)methyl)-2-thiophenecarboxamide; D000577:Amides; D000631:Aminopyridines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D013876:Thiophenes; D062367:ortho-Aminobenzoates