(2R)-4-Oxo-4[3-(Trifluoromethyl)-5,6-diihydro:1,2,4}triazolo[4,3-a}pyrazin-7(8H)-y1]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

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)-y...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-11, Vol.48 (2005)
Main Authors: Kim, D., Wang, L., Beconi, M., Eiermann, G., Fisher, M., He, H., Hickey, G., Kowalchick, Jennifer, Leiting, Barbara, Lyons, K., Marsilio, F., McCann, F., Patel, R., Petrov, A., Scapin, G., Patel, S., Roy, R., Wu, J., Wyvratt, M., Zhang, B., Zhu, L., Thornberry, N., Weber, A.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
AMIDES
AMINES
DIABETES MELLITUS
ENZYME INHIBITORS
NONSPECIFIC PEPTIDASES
PHOSPHATES
SYNTHESIS
TESTING
THERAPY
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Summary: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{sub 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.
ISSN:0022-2623
1520-4804