The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design. Issue 23 (1st December 2017)

• Record Type: Journal Article
• Authors: Forster, Ashley B.; Abeywickrema, Pravien; Bunda, Jaime; Cox, Christopher D.; Cabalu, Tamara D.; Egbertson, Melissa; Fay, John; Getty, Krista; Hall, Dawn; Kornienko, Maria; Lu, Jun; Parthasarathy, Gopal; Reid, John; Sharma, Sujata; Shipe, William D.; Smith, Sean M.; Soisson, Stephen; Stachel, Shawn J.; Su, Hua-Poo; Wang, Deping; Berger, Richard
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 23(2017)
• Page Start: 5167
• Page End: 5171
• Publication Date: 2017-12-01
• Subjects: PDE2 -- Phosphodiesterase 2 -- Fragment-based screening -- Structure-based drug design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.10.054
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.