Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood–brain-barrier
| Autor: | Cooper Martin, Pia Karina Nørregaard, Jean-Michel Linget, Emelie Bjurling, Jean-Marie Receveur, Peter Aadal Nielsen, Anthony Murray, Thomas Högberg |
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| Rok vydání: | 2010 |
| Předmět: |
Drug Inverse Agonism
Nitrile medicine.drug_class Clinical Biochemistry Pharmaceutical Science Carboxamide Pharmacology Pyrazole Biochemistry Polar surface area Mice Structure-Activity Relationship chemistry.chemical_compound Piperidines Receptor Cannabinoid CB1 Rimonabant Amide Drug Discovery medicine Animals Inverse agonist Obesity Molecular Biology ADME Body Weight Organic Chemistry Amides Rats chemistry Blood-Brain Barrier Pyrazoles Molecular Medicine Anti-Obesity Agents Protein Binding medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 20:453-457 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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