Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors

Ning Li; Li-Jun Wang; Bo Jiang; Shu-Ju Guo; Xiang-Qian Li; Xue-Chun Chen; Jiao Luo; Chao Li; Yi Wang; Da-Yong Shi

doi:10.1016/j.bmcl.2018.05.022

Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2131-2135. doi: 10.1016/j.bmcl.2018.05.022. Epub 2018 May 16.

Authors

Ning Li¹, Li-Jun Wang², Bo Jiang², Shu-Ju Guo², Xiang-Qian Li², Xue-Chun Chen³, Jiao Luo¹, Chao Li¹, Yi Wang⁴, Da-Yong Shi⁵

Affiliations

¹ Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China; University of Chinese Academy of Sciences, Beijing 100049, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China.
² Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China.
³ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
⁴ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: mysky@zju.edu.cn.
⁵ Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China; University of Chinese Academy of Sciences, Beijing 100049, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China. Electronic address: shidayong@qdio.ac.cn.

PMID: 29773502
DOI: 10.1016/j.bmcl.2018.05.022

Abstract

A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC₅₀ values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure-activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.

Keywords: DPP-4 inhibitor; Molecular hybrid; Pyrimidinedionederivatives; SARs; Type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental / drug therapy
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / metabolism
Dipeptidyl Peptidase 4 / metabolism*
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Glucose Tolerance Test
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Mice
Mice, Obese
Molecular Structure
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Structure-Activity Relationship

Substances

Dipeptidyl-Peptidase IV Inhibitors
Hypoglycemic Agents
Pyrimidinones
DPP4 protein, human
Dipeptidyl Peptidase 4