Design, Synthesis and Biological Evaluation of Imidazo[1, 2‐a]pyridine Derivatives as Novel DPP‐4 Inhibitors. (12th April 2015)

• Record Type: Journal Article
• Authors: Li, Qing; Zhou, Muxing; Han, Li; Cao, Qing; Wang, Xinning; Zhao, LeiLei; Zhou, Jinpei; Zhang, Huibin
• Is Part Of: Chemical biology & drug design. Volume 86:Number 4(2015:Oct.)
• Page Start: 849
• Page End: 856
• Publication Date: 2015-04-12
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12560
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12560-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>A new series of DPP‐4 inhibitors with imidazo[1, 2‐a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Based on docking binding model, structural modifications of 2‐benzene ring and pyridine moieties of compound <bold>5a</bold> led to the identification of compound <bold>5d</bold> with 2, 4‐dichlorophenyl group at the 2‐position as a potent (IC₅₀ = 0.13 <italic>μ</italic><sc>m</sc>), selective (DPP‐8/DPP‐4 = 215 and DPP‐9/DPP‐4 = 192) and <italic>in vivo</italic> efficacious DPP‐4 inhibitor. Further, molecular docking revealed that compound <bold>5d</bold> could retain key binding features of DPP‐4 with the pyridine moiety of imidazo[1, 2‐a]pyridine ring providing an additional <italic>π</italic>−<italic>π</italic> interaction with Phe357 of DPP‐4. Compound <bold>5d</bold> might be a promising lead for further development of novel DPP‐4 inhibitor treating T2DM.</p> </abstract>