Fatty acid binding proteins (FABPs) modulate intracellular levels of the endocannabinoid arachidonoyl ethanolamide (anandamide, AEA). Inhibition of tissue specific FABPs results in increased levels of brain AEA, which acts upon type-1 cannabinoid receptors (CB1R) and thereby causes a suppression of pain transmission and other therapeutically beneficial effects.<br/>Previous work by our group has identified SB-FI-26, a monoester analog of α-truxillic acid, as an inhibitor of the epidermal FABP (E-FABP, FABP5), and has shown both antinociceptive and anti-inflammatory effects in mice models.<br/>To optimize the lead compound, we have conducted an extensive SAR study to identify selective FABP5 inhibitors. Each analog was selected based on its docking energy score to FABP5 and selectivity against FABP3 and 7 isoforms, using the Autodock 4.2 program. Our computational model used the co-crystal structures of SB-FI-26 with FABP5 and FABP7, recently determined by us, and the apoprotein structure of FABP3. We have expanded our study to include compounds with the α, γ, and ε-truxillic acid scaffolds. The computational model we developed has disclosed structural features that affect the affinity to FABP5 and selectivity against FABP3 and 7 isoforms, which are very useful for drug design. The computer-aided design, synthesis and biological evaluations of a new series of FABP5 inhibitors will be discussed.

Design, synthesis, and biological evaluation of truxillic acid-based fatty acid binding protein 5 (FABP5) inhibitors as anti-nociceptive and anti-inflammatory agents

2019 Spring National Meeting

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