Title:Synthesis of β-Amino Carbonyl 6-(Aminomethyl)- and
6-(Hydroxymethyl)pyrazolopyrimidines for DPP-4 Inhibition Study
Volume: 31
Issue: 22
Author(s): Cheng-Yen Chung, Ching-Chun Tseng, Sin-Min Li, Wei-Zheng Zeng, Yu-Ching Lin, Yu-Pei Hu, Wen-Ping Jiang, Guan-Jhong Huang, Henry J. Tsai and Fung Fuh Wong*
Affiliation:
- Phd Program for Biotech Pharmaceutical Industry,
China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan
- School of Pharmacy,
China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan
Keywords:
6-(aminomethyl)pyrazolopyrimidine, 6-(hydroxymethyl)pyrazolopyrimidine, pyrazolopyrimidine, DPP- 4 inhibitors, β-amino ester, β-amino amide, sitagliptin.
Abstract:
Background: Type-2 diabetes is a chronic progressive metabolic disease resulting
in severe vascular complications and mortality risk. Recently, DPP-4 inhibitors
had been conceived as a favorable class of agents for the treatment of type 2 diabetes due
to the minimal side effects.
Methods: Sitagliptin is the first medicine approved for the DPP-4 inhibitor. Its structure
involved three fragments: 2,4,5-triflorophenyl fragment pharmacophore, enantiomerically
β-amino carbonyl linker, and tetrahydrotriazolopyridine. Herein, we are drawn to the
possibility of substituting tetrahydrotriazolopyridine motif present in Sitagliptin with a series
of new fused pyrazolopyrimidine bicyclic fragment to investigate potency and safety.
Results: Two series of fused 6-(aminomethyl)pyrazolopyrimidine and 6-(hydroxymethyl)
pyrazolopyrimidine derivatives containing β-amino ester or amide as linkers
were successfully designed for the new DPP-4 inhibitors. Most fused 6-methylpyrazolopyrimidines
were evaluated against DPP-4 inhibition and selectivity capacity. Based
on research study, β-amino carbonyl fused 6-(hydroxymethyl)pyrazolopyrimidine possesses
the significant DPP-4 inhibition (IC50 ≤ 59.8 nM) and presents similar with Sitagliptin
(IC50 = 28 nM). Particularly, they had satisfactory selectivity over DPP-8 and
DPP-9, except for QPP.
Conclusion: β-Amino esters and amides fused 6-(hydroxymethyl)pyrazolopyrimidine
were developed as the new DPP-4 inhibitors. Those compounds with a methyl group or
hydrogen in N-1 position and methyl substituted group in C-3 of pyrazolopyrimidine moiety
showed better potent DPP-4 inhibition (IC50 = 21.4-59.8 nM). Furthermore, they had
satisfactory selectivity over DPP-8 and DPP-9 Finally, the docking results revealed that
compound 9n was stabilized at DPP-4 active site and would be a potential lead drug.
