A novel phosphodiesterase inhibitor for the treatment of chronic liver injury and metabolic diseases.

Abstract

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. 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. In conclusion, we synthesized and demonstrated that MDL3, a novel PDE4B and PDE5A inhibitor, presents a promising avenue of exploration for treating CLD.