Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists

Article abstract of DOI:10.1021/jm00398a028

A rational approach to the design of centrally acting agents is presented, based initially upon a comparison of the physicochemical properties of three typical histamine H₂ receptor antagonists which do not readily cross the blood-brain barrier with those of the three brain-penetrating drugs clonidine (6), mepyramine (7), and imipramine (8). A good correlation was found between the logarithms of the equilibrium brain/blood concentration ratios in the rat and the partition parameter, Δ log P, defined as log P (1-octanol/water) - log P (cyclohexane/water), which suggests that brain penetration might be improved by reducing overall hydrogen-bonding ability. This model has been employed as a guide in the design of novel brain-penetrating H₂ antagonists by the systematic structural modification of representatives of different structural types of H₂ antagonists. Although marked increases in brain penetration amongst congeners of cimetidine (1), ranitidine (9), and tiotidine (10) were achieved, no compound was found with an acceptable combination of H₂ antagonist activity (-log K(B) in the guinea pig atrium > 7.0) and brain penetration (steady-state brain/blood concentration ratio > 1.0). Conversely, structural modification of N-[[(piperidinylmethyl)phenoxy]propyl]acetamide (30) led to several potent, novel compounds which readily cross the blood-brain barrier. One of these, zolantidine (SK&F 95282, 41), whose -log K(B) is 7.46 and steady-state brain/blood ratio is 1.4, has been identified for use in studying histaminergic H₂ receptor mechanisms in brain. Comparison of Δ log P values with the logarithms of the brain/blood ratios for 20 structurally diverse compounds for which data became available confirms a highly significant correlation and supports the general validity of this model.