Fatty Acid Binding Protein 5 (FABP5) is a tissue specific transporter protein, expressed in cells of the central and peripheral nervous system, which facilitates the diffusion of endocannabinoids, N-acylethanolamides, and other lipids within the cytosol. The catabolism of endocannabinoid, Anandamide (AEA) is aided by FABP5 activity, and the increased levels of AEA act on cannabinoid 1 (CB1) receptors, eliciting analgesic and anti-inflammatory effects. Thus, FABP5 shows promise as a novel protein target for sustainable therapy for chronic pain and inflammation. Previous work by our group has identified SB-FI-26, a 1-naphthyl α-truxillic acid mono-ester (TAME), as a biologically active inhibitor of FABP5, exhibiting analgesic and anti-inflammatory effects in mouse models. Extensive SAR studies have been carried out to identify more potent and selective analogs of SB-FI-26, such as SB-FI-102 and SB-FI-103. In silico techniques such as docking and molecular dynamics simulations have been used to predict the affinity and stability of potential drug candidates, as well as elucidate the interactions of well performing modifications. X-ray co-crystal structures of SB-FI-26 with FABP5 and FABP7, recently determined by us, serve as excellent models for these calculations and design. A co-crystal structure of FABP3 is also available with natural ligand oleic acid bound. Our models have disclosed structural and physicochemical features which improve potency in FABP5 and exhibit selectivity against FABP3 and FABP7, promoting the design and synthesis of novel analogs. Herein, we will report a new series of potent TAME-based FABP5 inhibitors, their predicted efficacy and pharmacological properties, chemical synthesis, biological evaluations and SAR.

Design, synthesis, and biological evaluation of the inhibitors of fatty acid binding protein 5 (FABP5) as next-generation therapeutics for chronic pain and inflammation

2019 Fall National Meeting

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