RESUMO
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
Assuntos
Ácidos Graxos não Esterificados/sangue , Pirazóis/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Animais , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/uso terapêutico , Masculino , Niacina/farmacologia , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Estereoisomerismo , Vasodilatadores/farmacologiaRESUMO
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.
Assuntos
Pirazóis/química , Receptores Acoplados a Proteínas G/agonistas , Tetrazóis/química , Vasodilatadores/química , Animais , Cães , Haplorrinos , Humanos , Camundongos , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Tetrazóis/síntese química , Tetrazóis/farmacocinética , Vasodilatadores/síntese química , Vasodilatadores/farmacocinéticaRESUMO
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.
Assuntos
Hipolipemiantes/farmacologia , Pirazóis/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Tetrazóis/farmacocinética , Adipócitos/efeitos dos fármacos , Animais , Ácidos Graxos não Esterificados/sangue , Humanos , Hipolipemiantes/síntese química , Hipolipemiantes/uso terapêutico , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirazóis/síntese química , Receptores Nicotínicos , Tetrazóis/síntese química , Vasodilatação/efeitos dos fármacosRESUMO
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.
Assuntos
Benzoatos/química , Ácidos Nicotínicos/química , Receptores Acoplados a Proteínas G/agonistas , Animais , 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/fisiologia , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/fisiologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Ácidos/química , Flúor/química , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Ácidos Graxos/metabolismo , Ligantes , Masculino , Camundongos , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Pirazóis/síntese química , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Ácidos Heterocíclicos/química , Química Farmacêutica/métodos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Receptores Nicotínicos/química , Adipócitos/metabolismo , Animais , AMP Cíclico/metabolismo , Desenho de Fármacos , Humanos , Cinética , Modelos Químicos , Niacina/química , Pirazóis/química , Ratos , Baço/metabolismoRESUMO
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.