RESUMO
Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.
Assuntos
Amidas/química , Amidas/farmacologia , Inibidores da Dipeptidil Peptidase IV , Piperazinas/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Amidas/síntese química , Amidas/farmacocinética , Animais , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Modelos Moleculares , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , RatosRESUMO
PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Proteínas Tirosina Fosfatases/química , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , DNA/química , DNA Complementar/metabolismo , Escherichia coli/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Leucina/química , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Mutagênese , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Recombinantes/química , Valina/químicaRESUMO
A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.