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

Article Details

Citation
Copy to clipboard

Receveur JM, Murray A, Linget JM, Norregaard PK, Cooper M, Bjurling E, Nielsen PA, Hogberg T

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

Bioorg Med Chem Lett. 2010 Jan 15;20(2):453-7. doi: 10.1016/j.bmcl.2009.12.003. Epub 2009 Dec 4.

PubMed ID
20015647 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
RimonabantCannabinoid receptor 1IC 50 (nM)4.5N/AN/ADetails
RimonabantCannabinoid receptor 1IC 50 (nM)2.9N/AN/ADetails
RimonabantCannabinoid receptor 1IC 50 (nM)5.1N/AN/ADetails