Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin

Jizhe Dong; Yanchun Gong; Jun Liu; Xiangfeng Chen; Xiaoan Wen; Hongbin Sun

doi:10.1016/j.bmc.2013.12.061

Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin

Bioorg Med Chem. 2014 Feb 15;22(4):1383-93. doi: 10.1016/j.bmc.2013.12.061. Epub 2014 Jan 7.

Authors

Jizhe Dong¹, Yanchun Gong¹, Jun Liu¹, Xiangfeng Chen², Xiaoan Wen³, Hongbin Sun⁴

Affiliations

¹ State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
² Nanjing Haiguang Applied Chemistry Institute, Jiangsu Aosaikang Pharmaceutical Co. Ltd, Nanjing 211112, China.
³ State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
⁴ State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].

PMID: 24457090
DOI: 10.1016/j.bmc.2013.12.061

Abstract

All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.

Keywords: Configuration–activity relationship; DPP-IV inhibitors; Saxagliptin; Stereoisomers; Synthesis.

MeSH terms

Adamantane / analogs & derivatives*
Adamantane / chemical synthesis
Adamantane / chemistry
Adamantane / pharmacology
Binding Sites
Catalytic Domain
Dipeptides / chemical synthesis
Dipeptides / chemistry*
Dipeptides / pharmacology
Dipeptidyl Peptidase 4 / chemistry
Dipeptidyl Peptidase 4 / metabolism*
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / metabolism
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Enzyme Activation / drug effects
Molecular Docking Simulation
Protein Binding
Stereoisomerism
Structure-Activity Relationship

Substances

Dipeptides
Dipeptidyl-Peptidase IV Inhibitors
saxagliptin
Dipeptidyl Peptidase 4
Adamantane