Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Abstract Phosphodiesterase 4 ( PDE 4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE 4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐ QSAR ) models on our previous reported catecholic PDE 4 inhibitors was built with a statistically significant cross‐validated coefficient ( q 2 ), conventional coefficient ( r 2 ), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (Co MFA ) and comparative molecular similarity index analysis (Co MSIA ) methods. Based on the analysis of Co MFA and Co MSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE 4B1 and PDE 4D7 with mid‐nanomolar IC 50 values and potential anti‐neuroinflammation activity in BV ‐2 cells. Docking simulation of compound 16a in the PDE 4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “ V ‐shaped” conformation, extending the side chain to S‐pocket.