Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis.
Through structure-based drug design and parallel synthesis, we have discovered a novel series of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines as guanidine bioisosteres. These compounds have been found to be highly potent, highly selective, and orally bioavailable.
Lu
Tianbao
T
3-Dimensional Pharmaceuticals, Inc., 665 Stockton Drive, Exton, PA 19341, USA. tlu3@prdus.jnj.com
Markotan
Thomas
T
Coppo
Frank
F
Tomczuk
Bruce
B
Crysler
Carl
C
Eisennagel
Stephen
S
Spurlino
John
J
Gremminger
Lisa
L
Soll
Richard M
RM
Giardino
Edward C
EC
Bone
Roger
R
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D013917:Thrombin