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Molecules 2016, 21(2), 185; doi:10.3390/molecules21020185

Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia
2
Department of Internal Medicine, Faculty of Medicine, Slovak Medical University, Limbová 12, SK-833 03 Bratislava, Slovakia
3
Department of Theoretical Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editor: James W. Gauld
Received: 11 January 2016 / Revised: 27 January 2016 / Accepted: 27 January 2016 / Published: 4 February 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1271 KB, uploaded 4 February 2016]   |  

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. View Full-Text
Keywords: density functional theory (DFT); anticoagulants; conformation; solvent effect; acidity; lipophilicity; absorption density functional theory (DFT); anticoagulants; conformation; solvent effect; acidity; lipophilicity; absorption
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Remko, M.; Remková, A.; Broer, R. Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors. Molecules 2016, 21, 185.

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