The ionization and lipophilicity properties of the second-generation catechol-O-methyltransferase (COMT) inhibitors entacapone (1), nitecapone (2), and tolcapone (3) which share the same nitrocatechol structure but have remarkably different pharmacokinetic profiles are investigated to identify relationships between some of these physicochemical parameters and the blood-brain-barrier (BBB) passage. In addition, the lipophilicity behavior of the simpler, structurally related analogues 4-11 is studied. Combined descriptors such as Delta log P (difference between log P in two different solvent systems) and diff(log PN-1) (difference between log P of two different electrical forms of a given solute in the same system) provide insight into inter- and intramolecular interactions characteristic of the analyzed compounds.