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

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-09-23 DOI:10.1007/s11030-024-10991-w

Zongmin Wu, Furong Zhang, Zhexin Chen, Xue Wang, Xingfu Liu, Guofeng Yang, Sen Wang, Shuheng Huang, Hai-Bin Luo, Yi-You Huang, Deyan Wu

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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.

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发现和优化作为新型磷酸二酯酶 4 抑制剂的 4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺衍生物。

磷酸二酯酶（PDEs）是一种重要的细胞内酶，可水解第二信使 cAMP 和/或 cGMP。目前已有多项研究表明，PDE4 受到了特别关注，因为它是涉及多种疾病的最主要的 cAMP 代谢酶。在这项研究中，我们对内部化合物库进行了预筛选，发现了具有中等 PDE4 抑制活性（IC50 为 4.78 ± 0.08 μM）的化合物（PTC-209）。以 PTC-209 为起点，采用基于结构的发现策略，成功设计并合成了一系列 4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺衍生物作为新型 PDE4 抑制剂。L19 是最有效的抑制剂，具有良好的抑制活性（IC50 为 0.48 ± 0.02 μM），并且在大鼠肝脏微粒体中具有显著的代谢稳定性。我们的研究为发现新型 PDE4 抑制剂提供了一个范例，有助于今后新型抑制剂的设计和优化。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;