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Demonstration of the Sequence Alignment to Predict Across Species Susceptibility Tool for Rapid Assessment of Protein Conservation
Published on: February 10, 2023
Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species
Shawn J Stachel1, Melissa S Egbertson1, Jenny Wai1
1Department of Medicinal Chemistry, 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.
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