Inhibition of fatty acid binding protein 5 (FABP5) elevates anandamide level resulting in suppression of pain transmission through type-1 cannabinoid receptor (CB1R). Thus, FABP5 is a promising target for anti-nociceptive and anti-inflammatory drug discovery and development. Furthermore, the inhibition of FABP5 is devoid of CB1R-dependent side effects. Our previous work identified a series of α-truxillic acid monoesters (α-TAMEs) as potent and selective FABPs inhibitors. Selective FABP5 inhibitors were able to effectively reverse the hyperalgesia in vivo. The present work aims at expanding the FABP5 inhibitor library to “truxilloids” through computer-aided drug design (CADD), synthesis and biological evaluations. Truxilloids include truxillic acid monoamides (TAMADs), monoethers (TAMETs) and monoamines (TAMAMs). A series of truxilloids were synthesized and their Ki values with FABP5, 3 and 7 were determined. TAMADs showed enhanced selectivity to FABP5 over FABP3 compared to TAMEs, while TAMETs showed similar selectivity profiles. Among these truxilloids, α-SBFI-10011N showed a remarkably higher FABP5/3 selectivity index (KiFABP5/KiFABP3: 3.3 to 114.4) than α-SBFI-10011 with only a slight reduction in KiFABP5. Molecular dynamics (MD) simulations and docking were performed to analyze the observed affinities and selectivity of truxilloids, and these results will be discussed. The in vivo efficacy of selected truxilloids and their pharmacological properties will also be presented. To assess the difference or indifference of enantiomers of TAMEs and truxilloids, we investigated kinetic resolution methods and devised an efficient protocol using chiral catalysts, which can provide α-TAMEs with 95% e.e. This protocol is applicable to the preparation of enantiopure α-TAMEs and α-TAMADs, as well as other truxilloids. The protocol and the biological evaluations of enantiopure truxilloids will be presented.

Design, synthesis, and biological evaluation of truxilloids as novel antinociceptive agents targeting fatty acid binding protein 5

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