(64f) Structure-Function Analysis of Phenylpiperazine Derivatives As Intestinal Permeation Enhancers

A major obstacle preventing oral administration of macromolecular therapeutics is poor absorption across the intestinal epithelium into the bloodstream. One strategy to improve transport across this barrier is the use of chemical permeation enhancers. (1) Several molecular families with permeation enhancing potential have been identified previously, including piperazines, which are molecules containing six-membered rings with two nitrogen atoms opposite each other in the ring. In particular, 1-phenylpiperazine has been shown to enhance transepithelial transport with minimal cytotoxicity compared to similarly effective permeation enhancing molecules. (2) To better understand how the chemistry of 1-phenylpiperazine affects its utility as an intestinal permeation enhancer, we examined a small library of 13 derivatives of 1-phenylpiperazine. The efficacy and cytotoxicity of 13 phenylpiperazine compounds were assessed in a Caco-2 model of the intestinal epithelium. Efficacy was measured using the paracellular diffusion marker calcein as well as by immunostaining and confocal imaging of Caco-2 monolayers. Of the 13 derivatives, several enhanced the permeability of the fluorescent marker calcein over 100-fold. It was found that hydroxyl or primary amine substitutions on the phenyl ring significantly increased toxicity, while aliphatic substitutions resulted in efficacy and toxicity profiles comparable to 1-phenylpiperazine. Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications. (3)

References:

(1) Aungst, B. J. (2012) Absorption Enhancers: Applications and Advances. AAPS J. 14, 10–18.

(2) Whitehead, K., Karr, N., and Mitragotri, S. (2008) Safe and effective permeation enhancers for oral drug delivery. Pharm. Res. 25, 1782-1788.

(3) Fein, K. C., Lamson, N. G., and Whitehead, K. A. (2017) Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers. Pharm. Res. 34, 1320–1329.