- 1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability.
1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability.
Bioorganic & medicinal chemistry letters (2011-04-05)
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
PMID21459572
摘要
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.