Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif.
2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K(i)=1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.
Kreutter
Kevin D
KD
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
Lu
Tianbao
T
Lee
Lily
L
Giardino
Edward C
EC
Patel
Sharmila
S
Huang
Hui
H
Xu
Guozhang
G
Fitzgerald
Mark
M
Haertlein
Barbara J
BJ
Mohan
Venkatraman
V
Crysler
Carl
C
Eisennagel
Stephen
S
Dasgupta
Malini
M
McMillan
Martin
M
Spurlino
John C
JC
Huebert
Norman D
ND
Maryanoff
Bruce E
BE
Tomczuk
Bruce E
BE
Damiano
Bruce P
BP
Player
Mark R
MR
D000081:Acetamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D000284:Administration, Oral; D020816:Amino Acid Motifs; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001665:Binding Sites; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000882:Haplorhini; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D009570:Nitriles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*
C529907:2-cyano-6-fluorophenylacetamide; D000081:Acetamides; D000925:Anticoagulants; D009570:Nitriles; D013917:Thrombin