Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species. Issue 6 (1st April 2018)

• Record Type: Journal Article
• Authors: Stachel, Shawn J.; Egbertson, Melissa S.; Wai, Jenny; Machacek, Michelle; Toolan, Dawn M.; Swestock, John; Eddins, Donnie M.; Puri, Vanita; McGaughey, Georgia; Su, Hua-Poo; Perlow, Debbie; Wang, Deping; Ma, Lei; Parthasarathy, Gopal; Reid, John C.; Abeywickrema, Pravien D.; Smith, Sean M.; Uslaner, Jason M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 6(2018)
• Page Start: 1122
• Page End: 1126
• Publication Date: 2018-04-01
• Subjects: PDE2 -- Schizophrenia -- Phosphodiesterase inhibitor -- Cognition -- Optimization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.01.039
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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, compound4, 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 of4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity. Abstract: 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, compound4, 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.