SAR study on Novel truxillic acid monoester-Based inhibitors of fatty acid binding proteins as Next-Generation antinociceptive agents

Fatty acid binding protein 5 (FABP5) is a highly promising target for the development of analgesics as its in-hibition is devoid of CB1R-dependent side-effects. The design and discovery of highly potent and FABP5-selective truxillic acid (TA) monoesters (TAMEs) is the primary aim of the present study. On the basis of molecular docking analysis, ca. 2,000 TAMEs were designed and screened in silico, to funnel down to 55 new TAMEs, which were synthesized and assayed for their affinity (Ki) to FABP5, 3 and 7. The SAR study revealed that the introduction of H-bond acceptors to the far end of the 1,1 '-biphenyl-3-yl and 1,1 '-biphenyl-2-yl ester moieties improved the affinity of alpha-TAMEs to FABP5. Compound gamma-3 is the first gamma-TAME, demonstrating a high affinity to FABP5 and competing with alpha-TAMEs. We identified the best 20 TAMEs based on the FABP5/3 selectivity index. The clear front runner is alpha-16, bearing a 2-indanyl ester moiety. In sharp contrast, no e-TAMEs made the top 20 in this list. However, alpha-19 and epsilon-202, have been identified as potent FABP3-selective inhibitors for applications related to their possible use in the protection of cardiac myocytes and the reduction of alpha-synuclein accumulation in Par-kinson's disease. Among the best 20 TAMEs selected based on the affinity to FABP7, 13 out of 20 TAMEs were found to be FABP7-selective, with alpha-21 as the most selective. This study identified several TAMEs as FABP7-selective inhibitors, which would have potentially beneficial therapeutic effects in diseases such as Down's syndrome, schizophrenia, breast cancer, and astrocytoma. We successfully introduced the alpha-TA monosilyl ester (TAMSE)-mediated protocol to dramatically improve the overall yields of alpha-TAMEs. alpha-TAMSEs with TBDPS as the silyl group is isolated in good yields and unreacted alpha-TA/ alpha-MeO-TA, as well as disilyl esters (alpha-TADSEs) are fully recycled. Molecular docking analysis provided rational explanations for the observed binding affinity and selectivity of the FABP3, 5 and 7 inhibitors, including their alpha, gamma and e isomers, in this study.