title: Small endogenous molecules as moiety to improve targeting of CNS drugs.
abstract: A major challenge in the development of novel neuro-therapeutic agents is to effectively overcome the blood-brain barrier (BBB), which acts as a 'working dynamic barrier'. The core problem in the treatment of neurodegenerative diseases is failed delivery of potential medicines due to their inadequate permeation rate. Areas covered: The present review gives a summary of endogenous moieties used in synthesizing prodrugs, derivatives and bioisosteric drugs appositely designed to structurally resemble physiological molecular entities able to be passively absorbed or carried by specific carrier proteins expressed at BBB level. In particular, this overview focuses on aminoacidic, glycosyl, purinergic, ureic and acidic fragments derivatives, most of which can take advantage from BBB carrier-mediated transporters, where passive diffusion is not permitted. Expert opinion: In the authors' perspective, further progress in this field could expedite successful translation of new chemical entities into clinical trials. Careful rationalization of the linkage between endogenous molecular structures and putative transporters binding sites could allow to useful work-flows and libraries for synthesizing new BBB-crossing therapeutic substances and/or multifunctional drugs for treatments of central disorders.
authors.affiliation: a Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF) , University of Palermo , via Archirafi 32, 90123 Palermo , Italy.
authors.forename: Flavia Maria
authors.initials: FM
authors.lastname: Sutera
authors.affiliation: a Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF) , University of Palermo , via Archirafi 32, 90123 Palermo , Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: De Caro
authors.affiliation: a Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF) , University of Palermo , via Archirafi 32, 90123 Palermo , Italy.
authors.forename: Libero Italo
authors.initials: LI
authors.lastname: Giannola
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002491:Central Nervous System Agents / Q000008:administration & dosage*; D004058:Diffusion; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D011355:Prodrugs
chemical_list: D002352:Carrier Proteins; D002491:Central Nervous System Agents; D026901:Membrane Transport Proteins; D011355:Prodrugs
keywords: BBB; CNS carriers; CNS prodrugs; bioisosteric drugs; multifunctional drugs; small endogenous molecules