Anandamide, an endocannabinoid, is linked to the regulation of stress, pain and inflammation. It activates cannabinoid receptors (CB receptors) on the cell surface, leading to the relief of pain and stress. Through diffusion, anandamide also enters the cell, where fatty acid binding protein 5 (FABP5) and fatty acid binding protein 7 (FABP7) transport the anandamide for inactivation by fatty acid amide hydrolase (FAAH). Inhibition of FABP5 and FABP7 would arrest the inactivation of the endocannabinoid, leading to higher extracellular anandamide levels, and resulting in anti-inflammatory and anti-nociceptive effects. Based on these observations, FABP5 and FABP7 would make good drug targets. Prior work from our laboratories has determined the crystal structures of FABP5 in complex with AEA, 2-AG, and SB-FI-26, the current lead compound. The structure of FABP5-SB-FI-26 co-crystal revealed that only one enantiomer of SB-FI-26 was present in the binding site of FABP5. This prompted the optical resolution of SB-FI-26, using various optical-resolution agents and solvent conditions, to determine if one enantiomer was indeed more active than the other. The two enantiomers were isolated and biologically evaluated. In addition, new SB-FI-26 analogues have been designed based on the crystal structure of the FABP5-SB-FI-26 complex, and synthesized to optimize potency and pharmacological properties. These analogues have various substitutions in the phenyl and the carboxylic acid moieties. The design and synthesis of novel α-truxillic acid derivatives, as well as optical resolution of SB-FI-26, their biological evaluations, and SAR studies will be presented.

Synthesis, optical resolution, and optimization of novel α-truxillic acid derivatives as anti-nociceptive and anti-inflammatory agents, targeting fatty acid binding protein (FABP)

251st National Meeting (2016)

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