(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

Journal Article · Wed Nov 10 00:00:00 EST 2010 · J. Med. Chem.

OSTI ID:1008488

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 ^[1]

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1. Merck

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE
• OSTI ID: 1008488
• Journal Information: J. Med. Chem., Vol. 48, Issue 2005; ISSN 0022-2623
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

60 APPLIED LIFE SCIENCES
AMINES
AMIDES
SYNTHESIS
ENZYME INHIBITORS
TESTING
NONSPECIFIC PEPTIDASES
DIABETES MELLITUS
THERAPY
PHOSPHATES