RESUMO
This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Desenho de Fármacos , Hipolipemiantes/síntese química , Quinolinas/química , Tetrazóis/síntese química , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/efeitos dos fármacos , HDL-Colesterol/metabolismo , Cães , Feminino , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Injeções Intravenosas , Masculino , Camundongos , Camundongos Transgênicos , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Naftiridinas/farmacologia , Animais , HDL-Colesterol , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Naftiridinas/síntese química , Relação Estrutura-AtividadeRESUMO
The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH2 to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over ß-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Administração Oral , Animais , Glicemia/análise , Descoberta de Drogas , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Camundongos , Modelos Moleculares , Ratos Sprague-DawleyRESUMO
Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.
Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/efeitos dos fármacos , Ligantes , Estrutura Molecular , Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest affinity. Resolution of the stereocenter of the benzylic piperazine based privileged structure revealed that the R-enantiomer was more active.