Publications by authors named "Hajime Nagashima"
The present study began with mathematical modeling of how inhibitors of both factor Xa (fXa) and thrombin affect extrinsic pathway-triggered blood coagulation. Numerical simulation demonstrated a stronger inhibition of thrombin generation by a thrombin inhibitor than a fXa inhibitor, but both prolonged clot time to a similar extent when they were given an equal dissociation constant (30 nm) for interaction with their respective target enzymes. These differences were then tested by comparison with the real inhibitors DX-9065a and argatroban, specific competitive inhibitors of fXa and thrombin, respectively, with similar K(i) values.
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- Four chiral forms of the beta-lactone DU-6622 were synthesized to study their effect on HMG-CoA synthase inhibition.
- The (2R,3R)-beta-lactone isomer (+)-8a exhibited the strongest inhibitory activity with an IC(50) of 0.098 μM, indicating high potency.
- The other isomers showed significantly weaker inhibition, with IC(50) values ranging from 9.4 μM to 360 μM, highlighting that the specific stereochemistry of the (2R,3R) form is crucial for effective HMG-CoA synthase inhibition.