Discovery of Peripherally Restricted Indazole-Based Phosphodiesterase 4B Inhibitors Targeting the C-terminal Regulatory Helix for Treating Acute Lung Injury

Acute lung injury (ALI), a life-threatening syndrome characterized by diffuse pulmonary inflammation and edema, currently lacks effective therapies. Although phosphodiesterase 4 (PDE4) is a promising therapeutic target for treating ALI, the clinical translation of its inhibitors is primarily limited by emetic side effects. To overcome this limitation, we designed and synthesized 36 indazole derivatives by targeting the C-terminal regulatory helix (CR3) of PDE4B and theoretically predicting blood-brain barrier (BBB) penetration for screening. Among these compounds, P32 was identified as a potent PDE4B inhibitor with minimal BBB penetration, reduced emetic risk, low systemic toxicity, and favorable pharmacokinetic properties. P32 significantly suppressed tumor necrosis factor-α production in macrophages and exerted therapeutic effects against ALI in animal models through its anti-inflammatory, antioxidant, and antiapoptotic activities. This study highlights indazole-based P32 as a peripherally restricted PDE4B inhibitor that targets the CR3 with a promising, safer therapeutic potential for treating ALI.