RESUMEN
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.
Asunto(s)
Pirazoles/química , Receptores Acoplados a Proteínas G/agonistas , Tetrazoles/química , Vasodilatadores/química , Animales , Perros , Haplorrinos , Humanos , Ratones , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Tetrazoles/síntesis química , Tetrazoles/farmacocinética , Vasodilatadores/síntesis química , Vasodilatadores/farmacocinéticaRESUMEN
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
The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
Asunto(s)
Hipolipemiantes/farmacología , Pirazoles/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Tetrazoles/farmacocinética , Adipocitos/efectos de los fármacos , Animales , Ácidos Grasos no Esterificados/sangre , Humanos , Hipolipemiantes/síntesis química , Hipolipemiantes/uso terapéutico , Lipólisis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Pirazoles/síntesis química , Receptores Nicotínicos , Tetrazoles/síntesis química , Vasodilatación/efectos de los fármacosRESUMEN
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.
Asunto(s)
Ácidos/química , Flúor/química , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Pirazoles/química , Pirazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Ácidos Grasos/metabolismo , Ligandos , Masculino , Ratones , Estructura Molecular , Agonistas Nicotínicos/síntesis química , Pirazoles/síntesis química , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Relación Estructura-ActividadRESUMEN
A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
Asunto(s)
Ácidos Heterocíclicos/química , Química Farmacéutica/métodos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Receptores Nicotínicos/química , Adipocitos/metabolismo , Animales , AMP Cíclico/metabolismo , Diseño de Fármacos , Humanos , Cinética , Modelos Químicos , Niacina/química , Pirazoles/química , Ratas , Bazo/metabolismoRESUMEN
1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a low-affinity receptor for the HDL-raising drug niacin. No activity was observed at the highly homologous high-affinity niacin receptor GPR109a (HM74A). The high degree of selectivity was attributed to a difference in the amino acid sequence adjacent to a key arginine-ligand interaction allowing somewhat larger ligands to be tolerated by GPR109b.