RESUMEN
A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.
Asunto(s)
Glucemia/efectos de los fármacos , Descubrimiento de Drogas , Oximas/síntesis química , Propano/análogos & derivados , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Oximas/química , Oximas/farmacología , Propano/sangre , Propano/síntesis química , Propano/química , Propano/farmacologíaRESUMEN
Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
Asunto(s)
Bencimidazoles/química , Receptores Citoplasmáticos y Nucleares/agonistas , para-Aminobenzoatos , Ácido 4-Aminobenzoico/síntesis química , Ácido 4-Aminobenzoico/química , Ácido 4-Aminobenzoico/farmacocinética , Administración Oral , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Conformación Molecular , Ratas , Ratas Wistar , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Relación Estructura-ActividadRESUMEN
Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.
Asunto(s)
Hipoglucemiantes/química , Hipolipemiantes/química , Receptores Citoplasmáticos y Nucleares/agonistas , Administración Oral , Animales , Sitios de Unión , Simulación por Computador , Diabetes Mellitus Experimental/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Dislipidemias/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipolipemiantes/administración & dosificación , Ratones , Ratones Noqueados , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Relación Estructura-ActividadRESUMEN
Potency with potential: 2-Phenoxy-nicotinamides were identified as potent agonists at the GPBAR1 receptor, a target in the treatment of obesity, type 2 diabetes and metabolic syndrome. Extensive structure-activity relationship studies supported by homology modeling and docking resulted in the identification of optimized GPBAR1 agonists, potent against both human and mouse receptors, endowed with favorable physicochemical properties and good metabolic stability.
Asunto(s)
Niacinamida/química , Receptores Acoplados a Proteínas G/agonistas , Sitios de Unión , Humanos , Simulación del Acoplamiento Molecular , Niacinamida/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Quinolinas/química , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.