Title of article :
Amidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors
Author/Authors :
Richard M. Soll، نويسنده , , Tianobao Lu، نويسنده , , Bruce Tomczuk، نويسنده , , Carl R. Illig، نويسنده , , Cynthia Fedde، نويسنده , , Stephen Eisennagel، نويسنده , , Roger Bone، نويسنده , , Larry Murphy، نويسنده , , John Spurlino، نويسنده , , F. Raymond Salemme، نويسنده ,
Abstract :
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.
