Identification of a brain penetrant PDE9A inhibitor utilizing prospective design and chemical enablement as a rapid lead optimization strategy

Patrick R Verhoest; Caroline Proulx-Lafrance; Michael Corman; Lois Chenard; Christopher J Helal; Xinjun Hou; Robin Kleiman; Shenping Liu; Eric Marr; Frank S Menniti; Christopher J Schmidt; Michelle Vanase-Frawley; Anne W Schmidt; Robert D Williams; Frederick R Nelson; Kari R Fonseca; Spiros Liras

doi:10.1021/jm9015334

Identification of a brain penetrant PDE9A inhibitor utilizing prospective design and chemical enablement as a rapid lead optimization strategy

J Med Chem. 2009 Dec 24;52(24):7946-9. doi: 10.1021/jm9015334.

Authors

Patrick R Verhoest¹, Caroline Proulx-Lafrance, Michael Corman, Lois Chenard, Christopher J Helal, Xinjun Hou, Robin Kleiman, Shenping Liu, Eric Marr, Frank S Menniti, Christopher J Schmidt, Michelle Vanase-Frawley, Anne W Schmidt, Robert D Williams, Frederick R Nelson, Kari R Fonseca, Spiros Liras

Affiliation

¹ Neuroscience Chemistry, Pfizer Global Research and Development, Groton, CT 06340, USA.

PMID: 19919087
DOI: 10.1021/jm9015334

Abstract

By use of chemical enablement and prospective design, a novel series of selective, brain penetrant PDE9A inhibitors have been identified that are capable of producing in vivo elevations of brain cGMP.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
3',5'-Cyclic-AMP Phosphodiesterases / chemistry
3',5'-Cyclic-AMP Phosphodiesterases / metabolism
Animals
Brain / enzymology*
Brain / metabolism
Cyclic GMP / metabolism
Humans
Hydrogen Bonding
Mice
Models, Molecular
Phosphodiesterase Inhibitors / chemistry
Phosphodiesterase Inhibitors / pharmacokinetics
Phosphodiesterase Inhibitors / pharmacology

Substances

Phosphodiesterase Inhibitors
3',5'-Cyclic-AMP Phosphodiesterases
PDE9A protein, human
Pde9a protein, mouse
Cyclic GMP