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

Summary for 3NOX

• Entry DOI: 10.2210/pdb3nox/pdb
• Related: 3BJM 3Q0T 3SWW 3SX4
• Descriptor: 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)
• Functional Keywords: 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
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 178895.25

Authors

Klei, H.E. (deposition date: 2010-06-25, release date: 2010-08-11, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.338 Å)