RESUMEN
The design and synthesis of indazolinone containing kinase inhibitors are reported. Regioisomers that showed profound potency variation in previously-reported isoindolinone and aminoindazole systems were surprisingly found to have similar potencies in the case of the indazolinone chemical series. An interpretation using differential hinge hydrogen bonding and tautomeric equilibrium of indazolinone ring system is supported by quantum mechanics calculations. The equipotent inhibition of a representative kinase (KDR) by regioisomeric indazolinones 4 and 5 is clear evidence that in case of the indazolinone hinge, both tautomers are equally favored, and should be considered in design of inhibitors.
Asunto(s)
Indazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Indazoles/farmacología , Isomerismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Indazoles/síntesis química , Indazoles/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/administración & dosificación , Humanos , Indazoles/administración & dosificación , Ratones , Piperidinas/química , Distribución TisularRESUMEN
The identification of a novel series of benzamide-containing MCHr1 antagonists is described. Compound 22 displayed moderate efficacy in a diet induced obesity mice model.
Asunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Benzamidas/química , Benzamidas/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/síntesis química , Benzamidas/síntesis química , Unión Competitiva , Modelos Animales de Enfermedad , Perros , Ratones , Estructura Molecular , Piperidinas/síntesis química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Factores de TiempoRESUMEN
The continued SAR investigation of 2-amino-8-alkoxy quinolines as melanin concentrating hormone receptor-1 (MCHr1) antagonists is reported. Prior hit-to-lead efforts resulted in the identification of 1 as a robust MCHr1 antagonist. Further delineation of the structural parameters essential for MCHr1-binding affinity of this class of nontraditional GPCR ligands resulted in the identification of compounds such as 33, 34 and 37, which demonstrate single digit nanomolar antagonism of MCHr1-mediated Ca(2+) release. The synthesis and biological evaluation of these compounds are reported.