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

…, MP Andrews, C Zarbo, ML Millham, BP Boscoe…

Index: DeNinno, Michael P.; Wright, Stephen W.; Visser, Michael S.; Etienne, John B.; Moore, Dianna E.; Olson, Thanh V.; Rocke, Benjamin N.; Andrews, Melissa P.; Zarbo, Cynthia; Millham, Michele L.; Boscoe, Brian P.; Boyer, David D.; Doran, Shawn D.; Houseknecht, Karen L. Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 10 p. 3095 - 3098

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Citation Number: 20

Abstract

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.