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

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; Fung Fuh Wong

doi:10.2174/0929867329666220614094305

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

Curr Med Chem. 2022 Jun 14. doi: 10.2174/0929867329666220614094305. Online ahead of print.

Authors

Cheng-Yen Chung¹, Ching-Chun Tseng^{2

3}, Sin-Min Li⁴, Wei-Zheng Zeng⁵, Yu-Ching Lin⁶, Yu-Pei Hu⁶, Wen-Ping Jiang⁷, Guan-Jhong Huang^{1

8}, Henry J Tsai⁸, Fung Fuh Wong^{2

3}

Affiliations

¹ Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan.
² Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan.
³ School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan.
⁴ Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan.
⁵ Master Program for Pharmaceutical Manufacture, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan.
⁶ Department of Biological Science and Technology, China Medical University, Taichung Taiwan.
⁷ Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
⁸ Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan.

PMID: 35702778
DOI: 10.2174/0929867329666220614094305

Abstract

Background: Type-2 diabetes is a chronic progressive metabolic disease resulting in severe vascular complications and mortality risk. Recently, DPP-4 inhibitors are 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 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.

Keywords: 6-(Aminomethyl)pyrazolopyrimidine; 6-(Hydroxymethyl)pyrazolopyrimidine; DPP-4 Inhibitors; Pyrazolopyrimidine; Sitagliptin; β-Amino amide; β-Amino ester.