Discovery of novel PDE4 degraders with in vivo anti-inflammatory efficacy.

Phosphodiesterase 4 (PDE4) has been identified to be an effective target for treatment of autoimmune and inflammatory diseases like chronic obstructive pulmonary disease (COPD), psoriasis and asthma. To overcome the selectivity problem, PDE4 degraders based on the proteolysis-targeting chimera (PROTAC) technology might be an alternative choose. Herein, a novel series of PDE4 PROTACs by recruiting Cereblon (CRBN) ligase were designed and synthesized. Among them, compound 9 m could suppress the secretion of pro-inflammatory cytokines such as TNF-α and IL-6 in LPS-stimulated Raw264.7 cells (IC50 = 43.25 μM, 53.79 μM). More importantly, 9 m could degrade PDE4B selectively (DC50 = 41.98 μM). Furthermore, we discovered that 9 m significantly reduced the infiltration of inflammatory cells into lung tissue to protect lung tissues and alleviate acute lung injury (ALI). Besides, 9 m exhibits moderate oral bioavailability (F%) of 21 %. Taken together, 9 m represents a novel PDE4 degrader deserving further development as a new lead compound for inflammatory diseases.