In:
International Journal of Quantum Chemistry, Wiley, Vol. 102, No. 5 ( 2005-01), p. 542-553
Kurzfassung:
Thrombin inhibition is an important strategy for the treatment of thrombotic and embolic disorders. Despite high in vitro affinity for the enzyme, synthetic thrombin inhibitors have limited oral bioavailability due to low intestinal permeability. In a previous work, we obtained the following order for thrombin binding by using molecular dynamics (MD) simulations and the finite difference thermodynamic integration (FDTI) method: p ‐(2‐oxo‐1‐propyl)benzamidine (POPBz) 〉 p ‐ethylbenzamidine (PEBz) 〉 p ‐(1‐propyl)benzamidine (PPBz) 〉 p ‐methylbenzamidine (PMBz) 〉 benzamidine (Bz). As the octanol/water partition coefficient (log P o/w ) is a thermodynamic property that may be related to drug transfer across biological membranes, we now turn our attention to the calculation by the FDTI method of relative log P o/w for the benzamidine derivatives. To examine the reliability of the method, log P o/w values for Bz and PMBz were determined experimentally. Experimental log P o/w of −1.02 and −0.89 were obtained for Bz and PMBz, and theoretical log P o/w of −0.12, −0.01, and −1.00 were obtained for PEBz, PPBz, and POPBz. Thus, we improved the hydrophobicity of Bz by adding the methyl, ethyl, propyl, and 2‐oxo‐propyl groups, but further substitutions should be conducted to raise log P o/w above zero and into a region where reasonable oral absorption might be expected. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005
Materialart:
Online-Ressource
ISSN:
0020-7608
,
1097-461X
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2005
ZDB Id:
1475014-4
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