RESUMO
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.
Assuntos
Amidas/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Barreira Hematoencefálica/metabolismo , Humanos , Receptor CB1 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/química , Fármacos Antiobesidade/química , Barreira Hematoencefálica/metabolismo , Piperidinas/química , Pirazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Peso Corporal , Agonismo Inverso de Drogas , Camundongos , Obesidade/tratamento farmacológico , Piperidinas/síntese química , Piperidinas/farmacologia , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto , Relação Estrutura-AtividadeRESUMO
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.