(2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

被引:727
作者
Kim, D [1 ]
Wang, LP [1 ]
Beconi, M [1 ]
Eiermann, GJ [1 ]
Fisher, MH [1 ]
He, HB [1 ]
Hickey, GJ [1 ]
Kowalchick, JE [1 ]
Leiting, B [1 ]
Lyons, K [1 ]
Marsilio, F [1 ]
McCann, ME [1 ]
Patel, RA [1 ]
Petrov, A [1 ]
Scapin, G [1 ]
Patel, SB [1 ]
Roy, RS [1 ]
Wu, JK [1 ]
Wyvratt, MJ [1 ]
Zhang, BB [1 ]
Zhu, L [1 ]
Thornberry, NA [1 ]
Weber, AE [1 ]
机构
[1] Merck & Co Inc, Merck Res Labs, Rahway, NJ 07065 USA
关键词
D O I
10.1021/jm0493156
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 (IC50 = 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.
引用
收藏
页码:141 / 151
页数:11
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