Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood–brain-barrier

A series of amides, amidines and amidoximes have been made from the corresponding nitrile compounds, to provide potent antagonists and inverse agonists for the CB1 receptor with considerably lower lipophiliciy, higher polar surface area and improved plasma/brain ratios compared to the centrally acting rimonabant. Extensive investigations of ADME and in vivo pharmacological properties led to selection of the amide series and specifically the 4-(4-fluorophenyl)piperidin-4-ol derivative D4. A clear improvement in the peripheral profile over rimonabant was seen, although some contribution of central effect on the pronounced weight reduction in obese mice cannot be ruled out.

Graphical abstractThe amide D4 displayed a pronounced weight reduction in DIO mice comparable to the centrally acting rimonabant, but with a considerably lower exposure in brain.Figure optionsDownload full-size imageDownload as PowerPoint slide