Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin

Zeng-Wei Lai; Chunhong Li; Jun Liu; Lingyi Kong; Xiaoan Wen; Hongbin Sun

doi:10.1016/j.ejmech.2014.06.044

Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin

Eur J Med Chem. 2014 Aug 18:83:547-60. doi: 10.1016/j.ejmech.2014.06.044. Epub 2014 Jun 23.

Authors

Zeng-Wei Lai¹, Chunhong Li¹, Jun Liu², Lingyi Kong¹, Xiaoan Wen³, Hongbin Sun⁴

Affiliations

¹ State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
² Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
³ State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China. Electronic address: [email protected].
⁴ State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China. Electronic address: [email protected].

PMID: 24996141
DOI: 10.1016/j.ejmech.2014.06.044

Abstract

Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.

Keywords: Alogliptin; DPP-4 inhibitors; Diabetes; Hybrid compound design; Linagliptin.

Publication types

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

MeSH terms

Diabetes Mellitus, Type 2 / drug therapy
Dipeptidyl Peptidase 4 / chemistry
Dipeptidyl Peptidase 4 / metabolism*
Dipeptidyl-Peptidase IV Inhibitors / chemistry*
Dipeptidyl-Peptidase IV Inhibitors / metabolism
Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
Drug Design
Humans
Linagliptin
Models, Molecular
Piperidines / chemistry*
Piperidines / metabolism
Piperidines / pharmacology*
Piperidines / therapeutic use
Protein Conformation
Purines / chemistry*
Purines / metabolism
Purines / pharmacology*
Purines / therapeutic use
Quinazolines / chemistry*
Quinazolines / metabolism
Quinazolines / pharmacology*
Quinazolines / therapeutic use
Structure-Activity Relationship
Substrate Specificity
Uracil / analogs & derivatives*
Uracil / chemistry
Uracil / metabolism
Uracil / pharmacology
Uracil / therapeutic use

Substances

Dipeptidyl-Peptidase IV Inhibitors
Piperidines
Purines
Quinazolines
Linagliptin
Uracil
Dipeptidyl Peptidase 4
alogliptin