Bioorganic & Medicinal Chemistry Letters 2007-03-01

3-[2-((2S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-3-methyl-butyramide analogues as selective DPP-IV inhibitors for the treatment of type-II diabetes.

Mohane Selvaraj Coumar, Chung-Nien Chang, Chiung-Tong Chen, Xin Chen, Chia-Hui Chien, Ting-Yueh Tsai, Jai-Hong Cheng, Hsin-Yi Wu, Chia-Hung Han, Ssu-Hui Wu, Yu-Wen Huang, Tsu Hsu, Li-Jen Hsu, Yu-Sheng Chao, Hsing-Pang Hsieh, Weir-Torn Jiaang

Index: Bioorg. Med. Chem. Lett. 17(5) , 1274-9, (2007)

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Abstract

Based on the structures of NVP-DPP728 (1) and NVP-LAF237 (Vildagliptin, 2), three series of DPP-IV inhibitors were synthesized by linking substituted anilines, benzylamines, and phenylethylamines to (2S)-cyanopyrrolidine through a linker. More than 20 compounds were evaluated for their in vitro DPP-IV inhibition and selectivity profile over DPP-II, DPP8, and FAP enzymes. Selected compounds 5f and 7i showed in vivo plasma DPP-IV inhibition and inhibited glucose excursion in OGTT after oral administration in Wistar rats. Compound 5f (DPP-IV IC50 = 116 nM) has the potential for development as antidiabetic agent.