RESUMEN
Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties.
Asunto(s)
Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/agonistas , Animales , Flúor/química , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Niacina/síntesis química , Niacina/química , Niacina/farmacología , Piridinas/síntesis química , Piridinas/química , Ratas , Ratas Sprague-Dawley , Receptores NicotínicosRESUMEN
5-Alkyl and aryl-pyrazole-acids have been identified as a new class of selective, small-molecule, agonists of the human orphan G-protein-coupled receptor GPR109a, a high affinity receptor for the HDL-raising drug nicotinic acid.
Asunto(s)
Pirazoles/química , Receptores Acoplados a Proteínas G/agonistas , Animales , Ácidos Grasos/metabolismo , Humanos , Ratones , Niacina/química , Pirazoles/síntesis química , Pirazoles/farmacocinética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismoRESUMEN
Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
Asunto(s)
Ácidos Carboxílicos/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Ciclohexenos/química , Descubrimiento de Drogas , Oxadiazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Área Bajo la Curva , Unión Competitiva , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Evaluación Preclínica de Medicamentos , Ácidos Grasos no Esterificados/sangre , Humanos , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Químicos , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacocinética , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacosRESUMEN
Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.
Asunto(s)
Cicloparafinas/síntesis química , Rubor/inducido químicamente , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Hipolipemiantes/síntesis química , Niacina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , ortoaminobenzoatos/síntesis química , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Cicloparafinas/efectos adversos , Cicloparafinas/farmacología , Oído/irrigación sanguínea , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Hipolipemiantes/efectos adversos , Hipolipemiantes/farmacología , Técnicas In Vitro , Lipólisis , Masculino , Ratones , Ensayo de Unión Radioligante , Ratas , Receptores Nicotínicos , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacos , ortoaminobenzoatos/efectos adversos , ortoaminobenzoatos/farmacologíaRESUMEN
High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Receptores de Colecistoquinina/agonistas , Amidas/química , Animales , Fármacos Antiobesidad/química , Quimiocinas CC , Técnicas Químicas Combinatorias , Ingestión de Alimentos/efectos de los fármacos , Vaciamiento Vesicular/efectos de los fármacos , Humanos , Imidazoles/química , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.
Asunto(s)
Ciclohexenos/síntesis química , Ciclohexenos/farmacología , Ciclopentanos/síntesis química , Ciclopentanos/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Animales , Hidrocarburo de Aril Hidroxilasas/efectos de los fármacos , Ciclohexenos/química , Ciclohexenos/farmacocinética , Ciclopentanos/química , Ciclopentanos/farmacocinética , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Diseño de Fármacos , Humanos , Ratones , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacología , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinéticaRESUMEN
Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.