Design, Synthesis, and Evaluation of Selective PDE4 Inhibitors for the Therapy of Pulmonary Injury.

Pulmonary inflammation is the main cause of lung injury. Phosphodiesterase 4 (PDE4) is a promising anti-inflammatory target for the treatment of respiratory diseases. Herein, we designed and synthesized 43 compounds in two novel series of benzimidazole derivatives as PDE4 inhibitors. Among them, compound A5 showed highly selective inhibition of PDE4, good safety, and liver microsomal stability in vitro. A5 administration remarkably attenuated inflammatory infiltration and pathologic injury of the lung in models of acute lung injury in mice and chronic obstructive pulmonary disease (COPD) in mice. In addition, A5 enhanced sputum secretion, relieved cough in mice, and inhibited phosphorylation of p38 MAP kinase, an important protein in the regulation of lung injury. Overall, A5, as an effective PDE4 inhibitor without acute toxicity and gastrointestinal reaction, may be a potent candidate for the treatment of pulmonary injury.