Hydrogen-bonding. Part 36. Determination of blood brain distribution using octanol-water partition coefficients.
It is shown that the octanol-water partition coefficient (Poct) cannot be used to predict blood brain distribution (BB) rectilinearly, but can be combined with Abraham solute descriptors to yield a predictive regression equation, eq (15), in which the solute descriptors sigma alpha H2 and sigma beta H2 are the overall summation hydrogen-bond acidity and basicity respectively. It is also demonstrated that of the various predictive models now available, that of Abraham, Chadha and Mitchell, eq (14), still yields the best results on a new test set of drug molecules; where the other solute descriptors are: R2, an excess molar refraction; pi H2, the dipolarity/polarisability; and Vx the characteristic volume of McGowan. Thus, solute dipolarity/polarizability, hydrogen-bond acidity and hydrogen-bond basicity favour blood, and solute size favours brain. logBB = +0.055 + 0.203logPoct - 0.507 sigma alpha H2 - 0.500 sigma beta H2 n = 49 rho = 0.9491 sd = 0.201 F = 136.1 (15) logBB = -0.038 + 0.198R2 - 0.607 pi H2 - 0.715 alpha H2 - 0.698 beta H2 + 0.995Vx n = 57 rho = 0.9522 sd = 0.197 F = 99.2 (14)
Abraham
M H
MH
Department of Chemistry, University College London, UK.
Chadha
H S
HS
Mitchell
R C
RC
D001812:Blood-Brain Barrier / Q000502:physiology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006860:Hydrogen Bonding; D008956:Models, Chemical; D000442:Octanols; D012044:Regression Analysis; D012995:Solubility; D014867:Water
D000442:Octanols; D014867:Water