Assuntos
Cálcio/metabolismo , Pirazinas/farmacologia , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/fisiologia , Digitonina/farmacologia , Humanos , Leucócitos Mononucleares , Lipopolissacarídeos/farmacologia , Polimorfismo de Nucleotídeo Único/fisiologia , Serotonina/análogos & derivados , Serotonina/farmacologiaRESUMO
The synthesis, structure-activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6-18 represent a novel class of potent and selective CB(1) receptor antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4).
Assuntos
Fármacos Antiobesidade/síntese química , Pirazóis/síntese química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Conformação Molecular , Pirazóis/química , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The cannabinoid CB(1)/CB(2) receptor subtype selectivity in the 1,2-diarylimidazole-4-carboxamide series was boosted by fine-tuning its 5-substitution pattern. The presence of the 5-methylsulfonyl group in 11 led to a greater than approximately 840-fold CB(1)/CB(2) subtype selectivity. The compounds 10, 18 and 19 were found more active than rimonabant (1) in a CB(1)-mediated rodent hypotension model after oral administration. Our findings suggest a limited brain exposure of the P-glycoprotein substrates 11, 12 and 21.
Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Imidazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Sulfonas/química , Administração Oral , Aminoimidazol Carboxamida/síntese química , Aminoimidazol Carboxamida/química , Aminoimidazol Carboxamida/uso terapêutico , Animais , Modelos Animais de Doenças , Agonismo Inverso de Drogas , Hipotensão/tratamento farmacológico , Imidazóis/síntese química , Imidazóis/uso terapêutico , Camundongos , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/uso terapêuticoRESUMO
The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1-23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24-27 as two novel cannabinoid CB(1) receptor agonist classes were described. The target compounds elicited high affinities to the CB(1) as well as the CB(2) receptor and were found to act as CB(1) receptor agonists. The key compound 19 elicited potent CB(1) agonistic and CB(2) inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration.
Assuntos
Pirazóis/farmacologia , Receptor CB1 de Canabinoide/agonistas , Pirazóis/químicaRESUMO
The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB(2)/CB(1) selective cannabinoid CB(2) receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable logP and calculated polar surface area values. Compound 12 exhibited the highest CB(2) receptor affinity (K(i)=1.03 nM) in this series, as well as the highest CB(2)/CB(1) subtype selectivity (>9708-fold).
Assuntos
Imidazóis/síntese química , Imidazóis/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Animais , Células CHO , Canabinoides/antagonistas & inibidores , Canabinoides/metabolismo , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Ligação Proteica/fisiologia , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB1 receptor antagonists.