Molecular structure, lipophilicity, solubility, absorption, and polar surface area of novel anticoagulant agents

The methods of theoretical chemistry have been used to elucidate molecular properties of factor Xa inhibitors (rivaroxaban, apixaban, otamixaban, betrixaban, razaxaban, and DX-9065a) and direct inhibitor of thrombin (dabigatran). The geometries and energies of these drugs have been computed using HF/6-31G(d), Becke3LYP/6-31G(d) and Becke3LYP/6-31++G(d,p) model chemistries. In the case of the Xa inhibitors (rivaroxaban, apixaban, otamixaban, betrixaban, razaxaban, and DX-9065a) the fully optimized most stable conformers possess characteristic L-shape structure. Water has a remarkable effect on the geometry of the anticoagulants studied. The anticoagulant drugs exhibit the largest stability in solvent as expected. Computed partition coefficients (ALOGPS method) for drugs studied varied between 1.7 and 3.9. Neutral compounds are described as lipophilic drugs. Rivaroxaban is drug with lowest lipophilicity. The anticoagulants studied are only slightly soluble in water, their computed solubilities from interval between 5 and 70 mg/L are sufficient for fast absorption. Experimentally determined solubility of rivaroxaban (8 mg/L) is very well interpreted by calculation. Rivaroxaban with PSA value 88 belongs to the anticoagulants with increased absorption. Direct thrombin inhibitor dabigatran is molecule with high total number of proton donor and proton acceptor groups (15), high PSA (150) and lowest absorption of the compounds studied. (C) 2009 Elsevier B.V. All rights reserved.