Theoretical prediction of relative and absolute pKa values of aminopyridines

This work presents a study aimed at the theoretical prediction of pK(a) values of aminopyridines, as a factor responsible for the activity of these compounds as blockers of the voltage-dependent K+ channels. To cover a large range of pK(a) values, a total of seven substituted pyridines is considered as a calibration set: pyridine, 2-aminopyridine, 3 -aminopyridine, 4-aminopyridine, 2-chloropyridine, 3-chloropyridine, and 4-methylpirydine. Using ab initio G1, G2 and G3 extrapolation methods, and the CPCM variant of the Polarizable Continuum Model for solvation, we calculate gas phase and solvation free energies. pK(a) values are obtained from these data using a thermodynamic cycle for describing protonation in aqueous and gas phases. The results show that the relatively inexpensive G1 level of theory is the most accurate at predicting pK(a) values in aminopyridines. The highest standard deviation with respect to the experimental data is 0.69 pK(a) units for absolute values calculations. The difference increases slightly to 0.74 pK(a) units when the pK(a) is computed relative to the pyridine molecule. Considering only compounds at least as basic as pyridine (the values of interest for bioactive aminopyridines) the error falls to 0.10 and 0.12 pK(a) units for the absolute and relative computations, respectively. The technique can be used to predict the effect of electronegative substituents in the pK(a) of 4-AP, the most active aminopyridine considered in this work. Thus, 2-chloro and 3-chloro-4-aminopyridine are taken into account. The results show a decrease of the pK(a), suggesting that these compounds are less active than 4-AP at blocking the K+ channel. (C) 2006 Elsevier B.V. All rights reserved.