Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold.

ABSTRACT: Direct inhibition of coagulation factor Xa (FXa) carries significant promise for developing effective and safe anticoagulants. Although a large number of FXa inhibitors have been studied, each can be classified as either possessing a highly flexible or a rigid core scaffold. We reasoned that an intermediate level of flexibility will provide high selectivity for FXa considering that its active site is less constrained in comparison to thrombin and more constrained as compared to trypsin. We studied several core scaffolds including 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for direct FXa inhibition. Using a genetic algorithm-based docking and scoring approach, a promising candidate 23 was identified, synthesized, and found to inhibit FXa with a K(i) of 28 μM. Optimization of derivativ

SUBMITTER: Al-Horani RA 

PROVIDER: S-EPMC3408863 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature