Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437.

In this study, we have synthesized almost 80 analogs of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group and we have investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogs was a more potent inhibitor of anandamide uptake than WOBE437 ( 1 ). At the same time, a number of WOBE437 variants exhibited potencies in the sub-100 nM range with high selectivity over inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase; two compounds were virtually equipotent with 1 . Interestingly, profound activity differences were observed between analogs where either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group. Some of the compounds described here could be interesting departure points for the development of potent endocannabinoid uptake inhibitors with more drug-like properties.
PMID: 32369259 [PubMed - as supplied by publisher]

Source: ChemMedChem - May 4, 2020 Category: Chemistry Authors: Altmann KH, Mäder P, Bartholomäus R, Nicolussi S, Baumann A, Weis M, Chicca A, Rau M, Simão AC, Gertsch J Tags: ChemMedChem Source Type: research