RESUMO
We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors. Additional optimization led to the discovery of 10, which possesses higher free fraction in plasma and improved pharmacokinetic properties in rat and cyno compared to 2.
Assuntos
Descoberta de Drogas , Oxidiazóis/farmacologia , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Quinolinas/síntese química , Quinolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Compostos de Anilina/síntese química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Receptores Acoplados a Proteínas G/química , Relação Estrutura-AtividadeRESUMO
The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.