Abstract
The geometries and energies of factor Xa inhibitors edoxaban, eribaxaban, fidexaban, darexaban, letaxaban, and the dual factor Xa and thrombin inhibitors tanogitran and SAR107375 in both the gas-phase and aqueous solution were studied using the Becke3LYP/6-31++G(d,p) or Grimme’s B97D/6-31++G(d,p) method. The fully optimized conformers of these anticoagulants show a characteristic l-shape structure, and the water had a remarkable effect on the equilibrium geometry. According to the calculated pKa values eribaxaban and letaxaban are in neutral undissociated form at pH 7.4, while fidexaban and tanogitran exist as zwitterionic structures. The lipophilicity of the inhibitors studied lies within a large range of log P between 1 and 4. The dual inhibitor SAR107375 represents an improvement in structural, physicochemical and pharmacokinetic characteristics over tanogitran. At blood pH, SAR107375 predominantly exists in neutral form. In contrast with tanogitran, it is better absorbed and more lipophilic and active after oral application.
Highlights
During the last 65 years or so compounds from the vitamin K antagonists group have been the only available oral anticoagulants [1], but their use is complicated owing to wide inter-individual variability in dose requirements and their narrow therapeutic index [2,3]
Eribaxaban, and letaxaban are present in neutral undissociated form at pH 7.4
The data presented in this theoretical study were able to determine the stable conformations, solvent effect, acidity, lipophilicity, solubility, absorption, and polar surface area of seven direct fXa inhibitors and two dual fXa and thrombin inhibitors for which a relatively small amount of experimental physicochemical data exist, considering their pharmacological importance
Summary
During the last 65 years or so compounds from the vitamin K antagonists group (warfarin and its derivatives) have been the only available oral anticoagulants [1], but their use is complicated owing to wide inter-individual variability in dose requirements and their narrow therapeutic index [2,3]. Selective fXa and/or thrombin inhibitors are at various stages of development [4,5,6] Synthetic inhibitors such as betrixaban, razaxaban, eribaxaban, fidexaban, darexaban (YM150), letaxaban (TAK-442) are members of a new class of orally available fXa inhibitors. In the work presented here we used density functional calculations for the detailed investigation of the molecular structure of direct fXa inhibitors edoxaban, eribaxaban, fidexaban, darexaban (YM150), letaxaban (TAK-442) and the dual factor Xa and thrombin inhibitors tanogitran and SAR107375. Attention has been given to comparison of theoretical results with published experimental properties of these drugs in the light of present theories of their action These and previously studied anticoagulant drugs [11,12] have entered early and advanced stages of clinical development. The investigation of their molecular structures and physicochemical properties may contribute to understand the relationships between structure and activity and biological properties of novel anticoagulants
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
