Small endogenous molecules as moiety to improve targeting of CNS drugs

ABSTRACT

Introduction: 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.

KEYWORDS:

• BBB
• small endogenous molecules
• CNS prodrugs
• CNS carriers
• bioisosteric drugs
• multifunctional drugs

Article highlights

• The main issue in the treatment of neurodegenerative diseases is dealing with failed delivery of potential medicines due to their inadequate BBB permeation.

• Novel neuro-therapeutic agents require to be structurally designed for overcoming the BBB, which acts as a ‘working dynamic barrier’.

• Endogenous moieties can be useful in synthesizing prodrugs, derivatives and bioisosteric drugs able to be shuttled by specific proteins expressed at BBB level.

• By using prodrug or bioisosteric or conjugation approaches, several successful compounds have been synthesized and already approved by FDA/EMEA and marketed, including Gabapentin, Pregabalin, L-DOPA, Melevodopa and Melphalan. Other promising medicines, as AIT-082, DA-Phen, and an Estradiol-chemical delivery system are under preclinical/clinical evaluation.

• A careful rationalization of the linkage between endogenous molecular structures and putative transporters binding sites could allow to multifunctional drugs for treatments of a variety of central disorders.

This box summarizes key points contained in the article

Acknowledgments

The authors would like to thank Dr Guy Elvie and Professor Nicholas Bodor for kindly providing supporting information on Chemical Drug Targeting Systems.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.