2. Academic Validation
  3. Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors

Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors

  • Mol Divers. 2024 Sep 23. doi: 10.1007/s11030-024-10991-w.
Zongmin Wu # 1 2,  Furong Zhang # 1 2,  Zhexin Chen 1,  Xue Wang 1,  Xingfu Liu 1,  Guofeng Yang 1,  Sen Wang 1,  Shuheng Huang 1,  Hai-Bin Luo 1,  Yi-You Huang 3,  Deyan Wu 4
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
  • 2 School of Life and Health Sciences, Hainan University, Haikou, 570228, China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. hyyou@hainanu.edu.cn.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. wudeyan@hainanu.edu.cn.
  • # Contributed equally.
PMID: 39313709 DOI: 10.1007/s11030-024-10991-w
Abstract

Phosphodiesterases (PDEs) are important intracellular Enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing Enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC50 of 4.78 ± 0.08 μM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC50 of 0.48 ± 0.02 μM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.

Keywords

Inhibitors; Metabolic stability; Phosphodiesterase; Phosphodiesterase 4; Structural optimization.

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