Oxyguanidines: application to non-peptidic phenyl-based thrombin inhibitors.
Although thrombin has been extensively researched with many examples of potent and selective inhibitors, the key characteristics of oral bioavailability and long half-life have been elusive. We report here a novel series non-peptidic phenyl-based, highly potent, highly selective and orally bioavailable thrombin inhibitors using oxyguanidines as guanidine-mimetics.
Tomczuk
Bruce
B
3-Dimensional Pharmaceuticals, Inc., 665 Stockton Drive, Exton, PA 19341, USA. bruce.tomczuk@3dp.com
Lu
Tianbao
T
Soll
Richard M
RM
Fedde
Cynthia
C
Wang
Aihua
A
Murphy
Larry
L
Crysler
Carl
C
Dasgupta
Malini
M
Eisennagel
Stephen
S
Spurlino
John
J
Bone
Roger
R
D000284:Administration, Oral; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D004285:Dogs; D006146:Guanidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D051381:Rats; D012697:Serine Endopeptidases / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D001555:Benzene Derivatives; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D013917:Thrombin