RESUMEN
Benzimidazolone derivatives were discovered as novel CB2 selective agonists. Structure Activity Relationship (SAR) studies around them were examined to improve metabolic stability. Compound 39 exhibited excellent metabolic stability in human liver microsomes (HLM) and significant attenuation of the chronic colonic allodynia in the TNBS-treated rats by po administration.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Receptor Cannabinoide CB2/agonistas , Animales , Bencimidazoles/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Estructura Molecular , Ratas , Receptor Cannabinoide CB1/agonistas , Relación Estructura-ActividadRESUMEN
Previous studies have shown that cannabinoid 2 (CB(2))-receptor agonists might have analgesic effects on visceral hypersensitivity. To extend these results, we have determined the pharmacological characteristics of a newly designed CB(2) ligand, N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (PF-03550096), in vitro and in vivo. PF-03550096 showed high affinity to human (K(i) = 7.9 +/- 1.7 nM) and rat CB(2) receptors (K(i) = 47 +/- 5.6 nM). In a cell-based functional assay, PF-03550096 behaved as a full agonist and showed high selectivity for human CB(2) receptors. Orally administered PF-03550096 (3, 10 mg/kg) inhibited the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced decrease in colonic pain threshold with statistical significance. The inhibitory effect of PF-03550096 (10 mg/kg) was significantly reversed by a selective CB(2) antagonist, N-(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl-5-(4-chloro-3-methylphenyl)-1(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), while SR144528 itself did not modify colonic pain threshold. These results indicate that PF-03550096 is a potent CB(2) agonist and possesses efficacy in a rat model of visceral hypersensitivity.
Asunto(s)
Bencimidazoles/uso terapéutico , Síndrome del Colon Irritable/tratamiento farmacológico , Dolor/tratamiento farmacológico , Receptor Cannabinoide CB2/agonistas , Animales , Bencimidazoles/sangre , Bencimidazoles/farmacocinética , Células CHO , Canfanos/sangre , Canfanos/farmacocinética , Canfanos/farmacología , Línea Celular , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Humanos , Síndrome del Colon Irritable/inducido químicamente , Síndrome del Colon Irritable/metabolismo , Masculino , Dolor/inducido químicamente , Dolor/metabolismo , Pirazoles/sangre , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismo , Ácido TrinitrobencenosulfónicoRESUMEN
A novel potent NMDA-NR2B selective antagonist without the reactive metabolites formation issue was identified. Through this study, a close correlation between reactive metabolites formation and calculated HOMO energies of parent compounds was found.