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. (26th December 2018)

• Record Type: Journal Article
• Authors: Huang, Chang; Zhong, Qiu‐Ping; Tang, Lv; Wang, Hai‐Tao; Xu, Jiang‐Ping; Zhou, Zhong‐Zhen
• Is Part Of: Chemical biology & drug design. Volume 93:Number 4(2019)
• Page Start: 484
• Page End: 502
• Publication Date: 2018-12-26
• Subjects: 3D‐QSAR -- anti‐neuroinflammation -- molecular docking -- PDE4 inhibitors; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13438
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 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 (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3, 4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles16a–i was designed and synthesized. Among these compounds, compound16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC50 values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound16a in the PDE4 catalytic domain activity pocket revealed that compound16a maybe assumed a " V ‐shaped" conformation, extending the side chain to S‐pocket. Abstract : In this paper, a reliable 3D‐QSAR model on catecholic PDE4 inhibitors was successfully built with a statistically significant cross‐validated coefficient ( q 2 ), conventional coefficient ( r 2 ) and good predictive capabilities, using CoMFA and CoMSIA methods. And a series of 2‐(3, 4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles16a–i was designed and synthesized based on the analysis of CoMFA and CoMSIA contour maps. Among these compounds, compound16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomole IC50 values, and potential anti‐neuroinflammation activity in BV‐2 cells.