Increased lipophilicity and subsequent cell partitioning decrease passive transcellular diffusion of novel, highly lipophilic antioxidants

Oxidative stress is considered a cause or propagator of acute and chronic d isorders of the central nervous system. Novel 2,4-diamino-pyrrolo[2,3-d]pyr imidines are potent inhibitors of iron-dependent lipid peroxidation, are cy toprotective in cell culture models of oxidative injury, and are neuroprote ctive in brain injury and ischemia models. The selection of lead candidates from this series required that they reach target cells deep within brain t issue in efficacious amounts after oral dosing. A homologous series of 26 h ighly lipophilic pyrrolopyrimidines was examined using cultured cell monola yers to understand the structure-permeability relationship and to use this information to predict brain penetration and residence time. Pyrrolopyrimid ines were shown to be a more permeable structural class of membrane-interac tive antioxidants where transepithelial permeability was inversely related to lipophilicity or to cell partitioning. Pyrrole substitutions influence c ell partitioning where bulky hydrophobic groups increased partitioning and decreased permeability and smaller hydrophobic groups and more hydrophilic groups, especially those capable of weak hydrogen bonding, decreased partit ioning, and increased permeability. Transmonolayer diffusion for these memb rane-inter active antioxidants was limited mostly by desorption from the re ceiver-side membrane into the buffer. Thus, in this case, these in vitro ce ll monolayer models do not adequately mimic the in vivo situation by undere stimating in vivo bioavailability of highly lipophilic compounds unless acc epters, such as serum proteins, are added to the receiving buffer.