Amidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors.
We describe a new class of potent, non-amide-based small molecule thrombin inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs, respectively. Crystallographic analysis of 4 bound to thrombin confirmed the amindinohydrazone binding mode.
Soll
R M
RM
3-Dimensional Pharmaceuticals, Eagleview Corporate Center, Exton, PA 19341, USA. soll@3dp.com
Lu
T
T
Tomczuk
B
B
Illig
C R
CR
Fedde
C
C
Eisennagel
S
S
Bone
R
R
Murphy
L
L
Spurlino
J
J
Salemme
F R
FR
D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014361:Trypsin Inhibitors / Q000494:pharmacology
D000578:Amidines; D005343:Fibrinolytic Agents; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D013917:Thrombin