RESUMEN
Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
Asunto(s)
Epilepsia Tónico-Clónica/prevención & control , Oxadiazoles/farmacocinética , Pirimidinas/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Femenino , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Oxadiazoles/química , Oxadiazoles/uso terapéutico , Pirimidinas/química , Pirimidinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
Asunto(s)
Agonismo Inverso de Drogas , Receptores de Ghrelina/agonistas , Receptores de Ghrelina/antagonistas & inhibidores , Urea/análogos & derivados , Urea/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Receptores de Ghrelina/metabolismo , Relación Estructura-Actividad , Urea/químicaRESUMEN
Inhibition of 11ß-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11ß-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/farmacocinética , Niacinamida/análogos & derivados , Piperidinas/farmacología , Piperidinas/farmacocinética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/metabolismo , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Modelos Moleculares , Niacinamida/administración & dosificación , Niacinamida/metabolismo , Niacinamida/farmacocinética , Niacinamida/farmacología , Piperidinas/administración & dosificación , Piperidinas/metabolismo , Conformación Proteica , Ratas , Especificidad por SustratoRESUMEN
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Oxadiazoles/síntesis química , Animales , Diabetes Mellitus/tratamiento farmacológico , Diacilglicerol O-Acetiltransferasa/metabolismo , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Semivida , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Ligandos , Ratones , Obesidad/tratamiento farmacológico , Oxadiazoles/farmacocinética , Relación Estructura-Actividad Cuantitativa , RatasRESUMEN
The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.