N-Salicyloyl acidic amino acids are a promising colon-specific promoiety of riluzole against rat colitis

In our previous study, riluzole (RLZ) azo-linked to salicylic acid (RAS) was prepared as a colon-targeted RLZ prodrug against rat colitis. However, RAS was not a satisfactory colon-targeted prodrug because of its non-negligible systemic absorption, leading to low colonic delivery efficiency and the ability to limit the systemic absorption of RLZ. This study aimed to improve the colon specificity and anticolitic activity of RAS.

Salicylic acid (SA) was conjugated with the acidic amino acids aspartic acid (Asp) and glutamic acid (Glu) and subsequently azo-coupled with RLZ to yield Asp-conjugated RAS (RAS-Asp) and Glu-conjugated RAS (RAS-Glu).

Amino acid-conjugated RAS lowered the distribution coefficient and cell permeability of RAS while exhibiting a release profile of RLZ similar to that of RAS in the cecal contents. Upon oral gavage, amino acid-conjugated RAS delivered a larger amount of RLZ to the cecum than RAS. The ability of amino acid-conjugated RAS to limit the systemic absorption of RLZ was greater than that of RAS. No significant differences were observed in the colon-specific performance between RAS-Asp and RAS-Glu. In a DNBS-induced rat colitis model, amino acid-conjugated RAS was more effective than RAS in ameliorating colonic damage and inflammation and modulating the anti-inflammatory GSK3β-IL-10 pathway in the inflamed colon, without a significant difference between RAS-Asp and RAS-Glu.

Conjugation of acidic amino acids with RAS improved the colon specificity, anticolitic activity, and safety of RAS. N-Salicyloyl acidic amino acids may act as high-performance colon-specific promiety for a candidate drug modifiable to a colon-targeted prodrug with an azo bond as a colon-specific link.