Fatty acid binding proteins (FABPs) facilitate the transportation of various endogenous lipophilic molecules. Inhibition of FABP5 elevates anandamide level resulting in suppression of pain transmission, positioning FABP5 inhibitors as a new class of anti-nociceptive and anti-inflammatory agent. Our previous work has identified potent FABP5 inhibitors from the SAR study on a series of SBFI-26 analogs, α-truxillic acid monoesters (α-TAMEs), based on computer-aided drug design and docking analysis, chemical synthesis, and biological evaluations. The present work expanded the SAR study to develop more potent, more selective, and less lipophilic FABP5 inhibitors using molecular docking techniques to assess the predicted affinity of nearly 2,000 compounds of α-, γ-, and ε-TAMEs prior to synthesis. Among evaluated TAMEs, α-TAMEs have the best examples of FABP5 affinity and selectivity than the other two isoforms. Within this SAR study, compound α-SB-FI-10051 emerged as a potent and selective FABP5/7 dual inhibitor; compound α-SB-FI-1621 showed high selectivity against FABP3 and FABP7. Additionally, nine potent FABP3 inhibitors were identified in this work. Compound α-SB-FI-11091 exhibited high FABP3 affinity and selectivity. Twenty compounds exhibited a sub-micromolar affinity to FABP7. Compound α-SB-FI-10951 emerged as a potent and selective FABP7/5 dual inhibitor; compound γ-SB-FI-4-MeO-102 showed high selectivity against FABP3 and FABP5. In vivo pain model study in mice showed that α-SB-FI-1621 and γ-SB-FI-10011 were able to fully reverse the hyperalgesia at 20 mg/kg dose. During this study, there has been growing interest in FABP3 and FABP7 – related diseases. Potent and selective FABP3 and FABP7 inhibitors identified in this work would facilitate further investigation into the therapeutically beneficial effects of FABP3 and FABP7 inhibition in the field of myocardial diseases and neurological disorders, respectively. The SAR and computational docking analysis of the affinity and selectivity of these TAME-based FABP inhibitors will be discussed.

SAR study on novel truxillic acid monoesters targeting fatty acid binding proteins

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