RESUMEN
The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inflamación/tratamiento farmacológico , Microsomas Hepáticos/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirazoles/farmacología , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/química , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Inflamación/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Osteoartritis/metabolismo , Dolor/metabolismo , Pirazoles/administración & dosificación , Pirazoles/química , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of 5-N,N-disubstituted-5-aminopyrazole-3-carboxylic acids were prepared and found to act as highly potent and selective agonists of the G-Protein Coupled Receptor (GPCR) GPR109b, a low affinity receptor for niacin and some aromatic d-amino acids. Little activity was observed at the highly homologous higher affinity niacin receptor, GPR109a.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Animales , Aterosclerosis/tratamiento farmacológico , Células CHO , Ácidos Carboxílicos/farmacología , Química Farmacéutica/métodos , Cricetinae , Cricetulus , Diseño de Fármacos , Dislipidemias/tratamiento farmacológico , Humanos , Ligandos , Lipoproteínas HDL/química , Lipoproteínas LDL/química , Modelos Químicos , Niacina/química , Pirazoles/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Receptores NicotínicosRESUMEN
A series of 3-nitro-4-substituted-aminobenzoic acids were prepared and found to act as potent and highly selective agonists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and several analogues showed comparable activity to the nitroaryl series.
Asunto(s)
Benzoatos/química , Ácidos Nicotínicos/química , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzoatos/agonistas , Benzoatos/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Niacina/metabolismo , Ácidos Nicotínicos/agonistas , Ácidos Nicotínicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/fisiología , Relación Estructura-ActividadRESUMEN
A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.
