RESUMEN
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
Asunto(s)
Amidas/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/síntesis química , Pirazinas/síntesis química , Triazoles/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Perros , Prueba de Tolerancia a la Glucosa , Haplorrinos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacocinética , Piperazinas/farmacología , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Pirazinas/química , Pirazinas/farmacología , Triazoles/química , Triazoles/farmacología , Administración Oral , Animales , Sitios de Unión , Bioquímica/métodos , Glucemia/análisis , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Glucagón/sangre , Glucagón/efectos de los fármacos , Péptido 1 Similar al Glucagón , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/efectos de los fármacos , Conformación Proteica , Precursores de Proteínas/sangre , Precursores de Proteínas/efectos de los fármacos , Pirazinas/farmacocinética , Ratas , Fosfato de Sitagliptina , Relación Estructura-Actividad , Triazoles/farmacocinéticaRESUMEN
A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.
Asunto(s)
Amidas/química , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/química , Inhibidores de Proteasas/farmacología , Pirazinas/farmacología , Triazoles/química , Animales , Inhibidores de Proteasas/síntesis química , Pirazinas/química , Ratas , Fosfato de Sitagliptina , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
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.