RESUMO
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.
Assuntos
Indazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Indazóis/farmacologia , Isomerismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/síntese química , Benzamidas/síntese química , Ligação Competitiva , Modelos Animais de Doenças , Cães , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
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.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Indazóis/síntese química , Indazóis/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Humanos , Indazóis/administração & dosagem , Camundongos , Piperidinas/química , Distribuição TecidualRESUMO
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.