5I7U

Human DPP4 in complex with a novel tricyclic hetero-cycle inhibitor

Summary for 5I7U

• Entry DOI: 10.2210/pdb5i7u/pdb
• Descriptor: Dipeptidyl peptidase 4, 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: structure-based drug design, diabetes, dpp4 inhibitors, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 174553.61

Authors

Scapin, G. (deposition date: 2016-02-18, release date: 2016-06-08, Last modification date: 2024-10-16)

Primary citation

Wu, W.L.,Hao, J.,Domalski, M.,Burnett, D.A.,Pissarnitski, D.,Zhao, Z.,Stamford, A.,Scapin, G.,Gao, Y.D.,Soriano, A.,Kelly, T.M.,Yao, Z.,Powles, M.A.,Chen, S.,Mei, H.,Hwa, J.
Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.
Acs Med.Chem.Lett., 7:498-501, 2016

PubMed Abstract: In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.

PubMed: 27190600
DOI: 10.1021/acsmedchemlett.6b00027

Experimental method

X-RAY DIFFRACTION (1.95 Å)