2OAE

Crystal structure of rat dipeptidyl peptidase (DPPIV) with thiazole-based peptide mimetic #31

2OAE の概要

• エントリーDOI: 10.2210/pdb2oae/pdb
• 分子名称: Dipeptidyl peptidase 4, SULFATE ION, N-{[(3S,5S)-5-(1,3-THIAZOLIDIN-3-YLCARBONYL)PYRROLIDIN-3-YL]METHYL}-1,3-THIAZOLE-4-CARBOXAMIDE (3 entities in total)
• 機能のキーワード: serine-peptidase, inhibitor complex, hydrolase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Dipeptidyl peptidase 4 soluble form: Secreted. Cell membrane; Single-pass type II membrane protein: P14740
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 169097.66

構造登録者

Longenecker, K.L.,Shuai, Q.,Patel, J.,Wiedeman, P. (登録日: 2006-12-15, 公開日: 2007-02-27, 最終更新日: 2024-10-30)

主引用文献

Backes, B.J.,Longenecker, K.,Hamilton, G.L.,Stewart, K.,Lai, C.,Kopecka, H.,von Geldern, T.W.,Madar, D.J.,Pei, Z.,Lubben, T.H.,Zinker, B.A.,Tian, Z.,Ballaron, S.J.,Stashko, M.A.,Mika, A.K.,Beno, D.W.,Kempf-Grote, A.J.,Black-Schaefer, C.,Sham, H.L.,Trevillyan, J.M.
Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.
Bioorg.Med.Chem.Lett., 17:2005-2012, 2007

PubMed Abstract: A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.

PubMed: 17276063
DOI: 10.1016/j.bmcl.2007.01.026

実験手法

X-RAY DIFFRACTION (3 Å)