| Affiliation: | 1. Discovery Chemistry, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA;2. Target Protein Design, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA;3. PPDM Preclinical ADME, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA;4. Pharmacology, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA;5. Assay Development, Protein Science, 770 Sumneytown Pike, MRL, West Point, PA 19486, USA;6. Structural Chemistry, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA;7. Neuroscience, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA;8. Chemical Modeling & Informatics, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA |
| Abstract: | ![]()
We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Ki?=?22.4?μM), exhibited good binding efficiencies (LBE?=?0.49, LLE?=?4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties. |
