title: Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier.
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.
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Receveur
authors.forename: Anthony
authors.initials: A
authors.lastname: Murray
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Linget
authors.forename: Pia K
authors.initials: PK
authors.lastname: Nørregaard
authors.forename: Martin
authors.initials: M
authors.lastname: Cooper
authors.forename: Emelie
authors.initials: E
authors.lastname: Bjurling
authors.forename: Peter Aadal
authors.initials: PA
authors.lastname: Nielsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: 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
chemical_list: D000577:Amides; D019440:Anti-Obesity Agents; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant