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J Med Chem ; 48(15): 5025-37, 2005 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-16033281


Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.

Adamantano/análogos & derivados , Adamantano/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/síntese química , Dipeptidil Peptidase 4/metabolismo , Glicina/análogos & derivados , Glicina/síntese química , Hipoglicemiantes/síntese química , Inibidores de Proteases/síntese química , Adamantano/farmacologia , Animais , Disponibilidade Biológica , Glicemia/análise , Diabetes Mellitus Tipo 2/fisiopatologia , Dipeptídeos/farmacologia , Teste de Tolerância a Glucose , Glicina/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Insulina/sangue , Masculino , Camundongos , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Nitrilos/síntese química , Nitrilos/farmacologia , Prolina/análogos & derivados , Prolina/síntese química , Prolina/farmacologia , Inibidores de Proteases/farmacologia , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-Atividade
J Med Chem ; 47(10): 2587-98, 2004 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-15115400


A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.

Ciclopropanos/síntese química , Dipeptidil Peptidase 4/metabolismo , Inibidores Enzimáticos/síntese química , Nitrilos/síntese química , Prolina/análogos & derivados , Prolina/síntese química , Animais , Simulação por Computador , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Dipeptídeos/química , Dipeptidil Peptidase 4/química , Estabilidade de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Nitrilos/química , Nitrilos/farmacologia , Prolina/química , Prolina/farmacologia , Ratos , Ratos Zucker , Soluções