Membrane permeability related physicochemical properties of a novel γ-secretase inhibitor

Pharmaceutical profiling studies were conducted on a novel prototype gamma-secretase inhibitor, to determine the potential of its oral absorption. Such compounds can be of use in the treatment of Alzheimer's disease (AD). The studies included determination of solubility, dissociation constant (pK(a)), octanol/water partition coefficient (log P) and the capacity factor (k'(IAM)) on immobilized artificial membrane (IAM) chromatographic columns. The compound is very slightly solubility in water (120 +/- 50 mug/mL) but the solubility increased considerably in basic medium (270 +/- 60 mug/mL). The compound exhibited pK(a) of (10.36 +/- 0.11); and log P of (3.36 +/- 0.16) determined by shake-flask method and (3.31 +/- 0.01) determined by high performance liquid chromatography (HPLC). The experimentally determined log P values correlated well with the calculated one of 3.44. The observed log k'(IAM) value of (2.79 +/- 0.04) indicates that the compound can reasonably be expected to have high membrane permeability, and therefore, good absorption profile if taken orally. This conclusion is also supported by other parameters determined. (C) 2004 Elsevier B.V. All rights reserved.