RESUMEN
A series of novel 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides were investigated as dipeptidyl peptidase IV (DPP-4) inhibitors. Introduction of a 4-phenylthiazol-2-yl group showed highly potent DPP-4 inhibitory activity. Among various derivatives, (3R)-3-amino-N-(4-(4-phenylthiazol-2-yl)-tetrahydro-2H-thiopyran-4-yl)-4-(2,4,5-trifluorophenyl)butanamide 1,1-dioxide (30) reduced blood glucose excursion in an oral glucose tolerance test by oral administration.
Asunto(s)
Amidas/química , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Piranos/química , Tiazoles/química , Administración Oral , Amidas/síntesis química , Amidas/metabolismo , Animales , Glucemia/metabolismo , Células CACO-2 , Dipeptidil Peptidasa 4/sangre , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Ratones , Ratones Endogámicos ICR , Unión Proteica , Piranos/síntesis química , Piranos/metabolismo , Tiazoles/síntesis química , Tiazoles/metabolismoRESUMEN
Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.