- 3-[2-((2S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-3-methyl-butyramid e analogues as selective DPP-IV inhibitors for the treatment of type-II diabetes
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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.
- Coumar, Mohane Selvaraj,Chang, Chung-Nien,Chen, Chiung-Tong,Chen, Xin,Chien, Chia-Hui,Tsai, Ting-Yueh,Cheng, Jai-Hong,Wu, Hsin-Yi,Han, Chia-Hung,Wu, Ssu-Hui,Huang, Yu-Wen,Hsu, Tsu,Hsu, Li-Jen,Chao, Yu-Sheng,Hsieh, Hsing-Pang,Jiaang, Weir-Torn
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p. 1274 - 1279
(2008/02/02)
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- 2-[3-[2-[(25)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl] -1,2,3,4-tetrahydroisoquinoline: A potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV
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Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2- oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC50 values of 50 > 100 μM) and DPP-II (IC50 > 30 μM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development. 2006 American Chemical Society.
- Tsu, Hsu,Chen, Xin,Chen, Chiung-Tong,Lee, Shiow-Ju,Chang, Chung-Nien,Kao, Kuo-His,Coumar, Mohane Selvaraj,Yeh, Yen-Ting,Chien, Chia-Hui,Wang, Hsin-Sheng,Lin, Ke-Ta,Chang, Ying-Ying,Wu, Ssu-Hui,Chen, Yuan-Shou,Lu, I.-Lin,Wu, Su-Ying,Tsai, Ting-Yueh,Chen, Wei-Cheng,Hsieh, Hsing-Pang,Chao, Yu-Sheng,Jiaang, Weir-Torn
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p. 373 - 380
(2007/10/03)
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