Octanol-water partition: searching for predictive models.
The log n-octanol/water partition coefficient (log Po/w) still represents one of the most informative physicochemical parameters available to medicinal chemists. In the present work, principles, methodologies, and parameters are briefly reviewed for a variety of models developed to predict this parameter based on molecular structure. To include the developments of recent years, a total of more than 40 different approaches are mentioned with relevant bibliography within four major categories: group contribution methods, atomic contribution methods, molecular methods, and other physicochemical methods. To underscore once more the utility of this partition coefficient, a comprehensive and reevaluated correlation between log Po/w and in vivo permeability data of rat brain capillaries is included. Most deviants that fell below the trendline are those that have been recently found to be substrates for P-glycoprotein, a multidrug transporter that actively removes them from the brain. Accurate predictions of log Po/w may necessitate many parameters, but there is mounting evidence that molecular size and hydrogen bonding ability can account for a major part of the variance. Our recently developed, molecular size-based approach is reviewed, and it is argued that introduction of three-dimensionality allows the elimination of many empirically derived fragment constants without a significant deterioration of the predictive accuracy. A comparison of predictive power for six different methods on 145 molecules of interest for medicinal chemists is also included.
Buchwald
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P
Center for Drug Discovery, University of Florida, Health Science Center, P.O. Box 100497, Gainesville, Florida 32610-0497, USA.
Bodor
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N
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D000442:Octanols; D010599:Pharmacokinetics; D051381:Rats; D014867:Water
D000442:Octanols; D014867:Water