1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability

Michael P DeNinno; Stephen W Wright; Michael S Visser; John B Etienne; Dianna E Moore; Thanh V Olson; Benjamin N Rocke; Melissa P Andrews; Cynthia Zarbo; Michele L Millham; Brian P Boscoe; David D Boyer; Shawn D Doran; Karen L Houseknecht

doi:10.1016/j.bmcl.2011.03.022

1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability

Bioorg Med Chem Lett. 2011 May 15;21(10):3095-8. doi: 10.1016/j.bmcl.2011.03.022. Epub 2011 Mar 11.

Authors

Michael P DeNinno¹, Stephen W Wright, Michael S Visser, John B Etienne, Dianna E Moore, Thanh V Olson, Benjamin N Rocke, Melissa P Andrews, Cynthia Zarbo, Michele L Millham, Brian P Boscoe, David D Boyer, Shawn D Doran, Karen L Houseknecht

Affiliation

¹ Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. mike_deninno@sd.vrtx.com

PMID: 21459572
DOI: 10.1016/j.bmcl.2011.03.022

Abstract

The first highly potent and selective PDE8 inhibitors are disclosed. The initial tetrahydroisoquinoline hit was transformed into a nipecotic amide series in order to address a reactive metabolite issue. Reduction of lipophilicity to address metabolic liabilities uncovered an interesting diastereomer-dependent trend in turnover by human microsomes.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
Amides / chemical synthesis*
Amides / chemistry
Amides / pharmacology*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Ligands
Microsomes / drug effects*
Models, Molecular
Molecular Structure
Nipecotic Acids / chemistry*

Substances

Amides
Enzyme Inhibitors
Ligands
Nipecotic Acids
nipecotic acid
3',5'-Cyclic-AMP Phosphodiesterases
PDE8A protein, human