Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species.

Shawn J Stachel,Melissa S Egbertson,Jenny Wai,Michelle Machacek,Dawn M Toolan,John Swestock,Donnie M Eddins,Vanita Puri,Georgia McGaughey,Hua-Poo Su, Debbie Perlow,Deping Wang,Lei Ma,Gopal Parthasarathy,John C Reid,Pravien D Abeywickrema,Sean M Smith,Jason M Uslaner

Bioorganic & Medicinal Chemistry Letters（2018）

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摘要

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.

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关键词

PDE2,Schizophrenia,Phosphodiesterase inhibitor,Cognition,Optimization

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