Abstract
On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.
MeSH terms
-
Animals
-
Carbamates / chemical synthesis
-
Carbamates / chemistry
-
Carbamates / pharmacokinetics
-
Crystallography, X-Ray
-
Drug Design
-
Factor IXa / antagonists & inhibitors*
-
Factor IXa / chemistry
-
Hydrogen Bonding
-
Models, Molecular
-
Molecular Conformation
-
Protein Binding
-
Rats
-
Rats, Sprague-Dawley
-
Stereoisomerism
-
Structure-Activity Relationship
-
Thiophenes / chemical synthesis*
-
Thiophenes / chemistry
-
Thiophenes / pharmacokinetics
Substances
-
Carbamates
-
Thiophenes
-
benzothiophene
-
Factor IXa