Aminoacidic derivatives as novel CNS-targeted neurotherapeutics

Abstract

Drug delivery to the CNS is subject to the permeability limitations imposed by the BBB that regulates movements of actives in and out of the brain. During the drug discovery phase a key aspect could be the selection of the compounds properties crucial for brain penetration. Novel CNS-targeted neurotherapeutics should possess the optimal characteristics that allow passive diffusion through the BBB via the transcellular route, or have the structural features necessary to serve as a substrate for one of the endogenous transport systems of the BBB. An attractive and rewarding chemistry-based strategy, employed to increase the CNS transport of poorly penetrating therapeutic agents, is the transient chemical modification. This approach could improve physicochemical, biopharmaceutical, pharmacokinetic and drug delivery properties of active agents that overcome barriers to a drug’s usefulness. With the aim of mask functional groups and modify the physicochemical properties relevant to bioavailability, in this work CNS-actives were covalently linked to different aminoacidic moieties. The chemical structure of the derivatives and Log D were determined. Chemical stability was evaluated in simulated biological fluids. Enzymatic stability was assessed ex vivo. The effects of derivatives were observed in vitro and their availability was measured in rat brain tissue. Finally, cellular toxicity was established. Our data support that aminoacids could be considered as good masking agents for CNS-targeted drugs.