Background and Aims: Chronic liver disease (CLD) leads to approximately two million deaths annually. Cyclic adenosine monophosphate (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B (PDE4B) inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases. Approach and Results: Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease (ALD) and steatotic liver disease (SLD). We demonstrated that A-33 effectively ameliorated the signs and symptoms of CLD, resulting in significant decreases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride (TG) concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix (ECM) deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both PDE4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration. Conclusions: In conclusion, we synthesized and demonstrated that MDL3, a novel PDE4B and PDE5A inhibitor, presents a promising avenue of exploration for treating CLD.

中文翻译：

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一种治疗慢性肝损伤和代谢性疾病的新型磷酸二酯酶抑制剂


背景和目标：慢性肝病 (CLD) 每年导致约 200 万人死亡。长期以来，人们一直在研究环状单磷酸腺苷 (cAMP) 信号传导在肝损伤中的作用，特别是在调节脂肪酸 (FA) β-氧化和组织驻留淋巴细胞的促炎极化方面。磷酸二酯酶 4B (PDE4B) 抑制已被探索作为一种治疗方式，但这些药物的成功有限，并且已知会引起显着的副作用。 PDE4抑制剂2-(4-([2-(5-氯噻吩-2-基)-5-乙基-6-甲基嘧啶-4-基]氨基)苯基)乙酸)(称为A-33)尚未代谢性疾病的治疗有待探索。方法和结果：在此，我们评估了 A-33 在治疗酒精相关性肝病 (ALD) 和脂肪肝病 (SLD) 动物模型中的功效。我们证明 A-33 能有效改善 CLD 的体征和症状，导致血清丙氨酸转氨酶 (ALT) 和天冬氨酸转氨酶 (AST) 水平显着降低，减少肝脏中的总体脂肪和胶原沉积，降低肝内甘油三酯 (TG)浓度以及与脂肪酸 β-氧化、炎症和细胞外基质 (ECM) 沉积相关的基因的标准化表达。我们还设计并合成了一种新型 A-33 类似物，称为 MDL3，它可以抑制 PDE4B 和 PDE5A，并且更有效地改善肝损伤和炎症的病理生理体征和症状。此外，MDL3 使肥胖小鼠对葡萄糖重新敏感，并显着抑制脂肪组织的病理重塑，这是 A-33 给药时未观察到的。 结论：总而言之，我们合成并证明了 MDL3，一种新型 PDE4B 和 PDE5A 抑制剂，为治疗 CLD 提供了一条有希望的探索途径。