Several lipid chaperones, such as fatty acid binding protein (FABPs), exist in the mammalian genome which enable the diffusion of highly hydrophobic molecules across membranes. Inhibition of specific subtypes of FABPs has been demonstrated to provide potential therapeutic benefit for chronic pain and may also for certain cancers. In particular, the inhibition of FABP5 has been shown to elicit analgesia through inhibiting reuptake of anandamide, hence increasing its extracellular concentration to show physiological effects. By acting though the cannabinoid receptor, anandamide has also been shown to decrease inflammation. The prospect of a less addictive mechanism of action is especially desired due to the epidemic of prescription opioid associated overdose deaths. Based on the in-silico screening of over a million compounds from the ZINC database, followed by in vitro FABP-binding affinity assay, we have discovered a unique a-truxillic acid derivative, SB-FI-26, as a hit/lead compound. SB-FI-26 exhibited potent anti-nociceptive activities when tested in vivo in mice models of pain. The optimization of SB-FI-26 is actively underway in our laboratories. The same in-silico screening and in vitro affinity assay identified two more active hit compounds, SB-FI-19 and SB-FI-31. Therefore, in this study we performed structure-based computer-aided optimization of these two hit compounds for FABP5, which produced a series of analogs with promising docking energy scores and predicted pharmacological properties. The design, synthesis and biological evaluation of selected hit compounds will be presented.

Design, synthesis, and SAR of inhibitors of lipid chaperones (FABPs) toward next-generation therapeutic agents for chronic pain and cancer

256th National Meeting (2018)

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