ABSTRACT
A chemically diverse library of secondary and tertiary 4-cyanomethyl-1,5-diphenyl-1H-pyrazole-3-carboxamides was synthesized to enable mapping of the SAR, in the eastern amide region, with regard to CB1 antagonist activity, This study was initiated as a prelude to the design and synthesis of possible CB1 antagonists that do not readily pass the blood-brain-barrier. In general a range of modifications were found to be tolerated in this part of the molecule, although polar and especially charged groups did to a degree reduce the CB1 antagonistic activity. Several compounds with single-digit or even sub-nanomolar potency, suitable for further elaboration of the nitrile moiety, were identified.
Subject(s)
Amides/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Blood-Brain Barrier/metabolism , Humans , Receptor, Cannabinoid, CB1/metabolism , Small Molecule Libraries , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Blood-Brain Barrier/metabolism , Piperidines/chemistry , Pyrazoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Body Weight , Drug Inverse Agonism , Mice , Obesity/drug therapy , Piperidines/chemical synthesis , Piperidines/pharmacology , Protein Binding , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Rats , Receptor, Cannabinoid, CB1/metabolism , Rimonabant , Structure-Activity RelationshipABSTRACT
Synthesis, in vitro biological evaluation and structure-activity relationships of 4-acylamino-and 4-ureidobenzamides as novel hMCH1R-antagonists are disclosed. The nature of the amine side chains could be varied considerably in contrast to the central benzamide scaffold and aromatic substituents.
