The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design

Ashley B Forster; Pravien Abeywickrema; Jaime Bunda; Christopher D Cox; Tamara D Cabalu; Melissa Egbertson; John Fay; Krista Getty; Dawn Hall; Maria Kornienko; Jun Lu; Gopal Parthasarathy; John Reid; Sujata Sharma; William D Shipe; Sean M Smith; Stephen Soisson; Shawn J Stachel; Hua-Poo Su; Deping Wang; Richard Berger

doi:10.1016/j.bmcl.2017.10.054

The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5167-5171. doi: 10.1016/j.bmcl.2017.10.054. Epub 2017 Oct 23.

Authors

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

Affiliations

¹ Discovery Chemistry, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: Ashley_nomland@merck.com.
² Target Protein Design, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.
³ Discovery Chemistry, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.
⁴ PPDM Preclinical ADME, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.
⁵ Pharmacology, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.
⁶ Assay Development, Protein Science, 770 Sumneytown Pike, MRL, West Point, PA 19486, USA.
⁷ Structural Chemistry, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.
⁸ Neuroscience, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.
⁹ Chemical Modeling & Informatics, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA.

PMID: 29113762
DOI: 10.1016/j.bmcl.2017.10.054

Abstract

We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (K_i = 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.

Keywords: Fragment-based screening; PDE2; Phosphodiesterase 2; Structure-based drug design.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Catalytic Domain
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 2 / antagonists & inhibitors*
Cyclic Nucleotide Phosphodiesterases, Type 2 / metabolism
Drug Design*
Half-Life
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Conformation
Molecular Dynamics Simulation
Phosphodiesterase Inhibitors / chemistry*
Phosphodiesterase Inhibitors / metabolism
Phosphodiesterase Inhibitors / pharmacokinetics
Pyrazoles / chemistry
Pyrazoles / metabolism
Pyrazoles / pharmacokinetics
Pyrimidines / chemistry
Pyrimidines / metabolism
Pyrimidines / pharmacokinetics
Rats
Structure-Activity Relationship

Substances

Isoenzymes
Phosphodiesterase Inhibitors
Pyrazoles
Pyrimidines
pyrazolylpyrimidine
Cyclic Nucleotide Phosphodiesterases, Type 2