Synthesis of β-Amino Carbonyl 6-(Aminomethyl)- and 6-(Hydroxymethyl)pyrazolopyrimidines for DPP-4 Inhibition Study


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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.

About the authors

Cheng-Yen Chung

Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University,

Email: info@benthamscience.net

Ching-Chun Tseng

Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University,

Email: info@benthamscience.net

Sin-Min Li

Institute of New Drug Development,, China Medical University,

Email: info@benthamscience.net

Wei-Zheng Zeng

Master Program for Pharmaceutical Manufacture, China Medical University,

Email: info@benthamscience.net

Yu-Ching Lin

Department of Biological Science and Technology, China Medical University

Email: info@benthamscience.net

Yu-Pei Hu

Department of Biological Science and Technology,, China Medical University

Email: info@benthamscience.net

Wen-Ping Jiang

Department of Pharmacy,, Chia Nan University of Pharmacy and Science

Email: info@benthamscience.net

Guan-Jhong Huang

Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University,

Email: info@benthamscience.net

Henry Tsai

Department of Health and Nutrition Biotechnology, Asia University

Email: info@benthamscience.net

Fung Wong

Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University,

Author for correspondence.
Email: info@benthamscience.net

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