Design, Synthesis and Enhanced BBB Penetration Studies of L-serine-Tethered Nipecotic Acid-Prodrug

Abstract

Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial-aminobutyric acid (GABA) uptake in vitro. Due to its hydrophilic nature, nipecotic acid does not readily cross the blood-brain barrier (BBB). Large neutral amino acids (LAT1)-knotted nipecotic acid prodrug was designed and synthesized with the aim to enhance the BBB permeation by the use of carrier-mediated transport. The synthesized prodrug was tested in animal models of Pentylenetetrazole (PTZ)-induced convulsions in mice. Further pain studies were carried out followed by neurotoxicity estimation by writhing and rota-rod test respectively. HPLC data suggests that the synthesized prodrug has improved penetration through BBB. Nipecotic acid-L-serine ester prodrug with considerable anti-epileptic activity, and the ability to permeate the BBB has been successfully synthesized. Graphical Abstract.

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

“…The nipecotic acid prodrug greatly enhanced the brain transport of nipecotic acid, justifying the rationale of design (Figure 21). 123 Montaser et al developed four novel LAT1-utilizing prodrugs of four nonsteroidal anti-inflammatory drugs. The small-sized LAT1-utilizing prodrug of salicylic acid successfully delivered the parent drug across the BBB.…”