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.
Receveur
Jean-Marie
JM
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
Murray
Anthony
A
Linget
Jean-Michel
JM
Nørregaard
Pia K
PK
Cooper
Martin
M
Bjurling
Emelie
E
Nielsen
Peter Aadal
PA
Högberg
Thomas
T
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001835:Body Weight; D054314:Drug Inverse Agonism; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D013329:Structure-Activity Relationship
D000577:Amides; D019440:Anti-Obesity Agents; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant