Tsu_2006_J.Med.Chem_49_373

Reference

Title : 2-[3-[2-[(2S)-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 - Tsu_2006_J.Med.Chem_49_373
Author(s) : Tsu H , Chen X , Chen CT , Lee SJ , Chang CN , Kao KH , Coumar MS , Yeh YT , Chien CH , Wang HS , Lin KT , Chang YY , Wu SH , Chen YS , Lu IL , Wu SY , Tsai TY , Chen WC , Hsieh HP , Chao YS , Jiaang WT
Ref : Journal of Medicinal Chemistry , 49 :373 , 2006
Abstract :

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 IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). 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.

PubMedSearch : Tsu_2006_J.Med.Chem_49_373
PubMedID: 16392822

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Citations formats

Tsu H, Chen X, Chen CT, Lee SJ, Chang CN, Kao KH, Coumar MS, Yeh YT, Chien CH, Wang HS, Lin KT, Chang YY, Wu SH, Chen YS, Lu IL, Wu SY, Tsai TY, Chen WC, Hsieh HP, Chao YS, Jiaang WT (2006)
2-[3-[2-[(2S)-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
Journal of Medicinal Chemistry 49 :373

Tsu H, Chen X, Chen CT, Lee SJ, Chang CN, Kao KH, Coumar MS, Yeh YT, Chien CH, Wang HS, Lin KT, Chang YY, Wu SH, Chen YS, Lu IL, Wu SY, Tsai TY, Chen WC, Hsieh HP, Chao YS, Jiaang WT (2006)
Journal of Medicinal Chemistry 49 :373