| Literature DB >> 29113762 |
Ashley B Forster1, Pravien Abeywickrema2, Jaime Bunda3, Christopher D Cox3, Tamara D Cabalu4, Melissa Egbertson3, John Fay5, Krista Getty6, Dawn Hall2, Maria Kornienko2, Jun Lu7, Gopal Parthasarathy7, John Reid7, Sujata Sharma2, William D Shipe3, Sean M Smith8, Stephen Soisson7, Shawn J Stachel3, Hua-Poo Su7, Deping Wang9, Richard Berger3.
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.Entities:
Keywords: Fragment-based screening; PDE2; Phosphodiesterase 2; Structure-based drug design
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Year: 2017 PMID： 29113762 DOI： 10.1016/j.bmcl.2017.10.054
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823