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Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species |
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| Authors: | 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 |
| Affiliation: | 1. Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA;2. Department of Pharmacology, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA;3. Department of Structural Biology, Merck & Co. Inc, PO Box 4, West Point, PA 19486, USA;4. Department of Neuroscience, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA |
| 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, 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. |
| Keywords: | PDE2 Schizophrenia Phosphodiesterase inhibitor Cognition Optimization |
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