3NOX

Crystal structure of human DPP-IV in complex with Sa-(+)-(6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)(morpholino)methanone

3NOX の概要

• エントリーDOI: 10.2210/pdb3nox/pdb
• 関連するPDBエントリー: 3BJM 3Q0T 3SWW 3SX4
• 分子名称: Dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2), 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: exopeptidase, alpha/beta hydrolase fold, beta barrel, beta propeller, dpp4, dimer, protein:inhibitor complex, aminopeptidase, glycoprotein, membrane, protease, secreted, serine protease, signal-anchor, transmembrane, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 178895.25

構造登録者

Klei, H.E. (登録日: 2010-06-25, 公開日: 2010-08-11, 最終更新日: 2024-10-30)

主引用文献

Meng, W.,Brigance, R.P.,Chao, H.J.,Fura, A.,Harrity, T.,Marcinkeviciene, J.,O'Connor, S.P.,Tamura, J.K.,Xie, D.,Zhang, Y.,Klei, H.E.,Kish, K.,Weigelt, C.A.,Turdi, H.,Wang, A.,Zahler, R.,Kirby, M.S.,Hamann, L.G.
Discovery of 6-(Aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as Potent, Selective Dipeptidyl Peptidase-4 (DPP4) Inhibitors.
J.Med.Chem., 53:5620-5628, 2010

PubMed Abstract: Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.

PubMed: 20684603
DOI: 10.1021/jm100634a

実験手法

X-RAY DIFFRACTION (2.338 Å)