1. Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors
- Author
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Heather Twin, Chau Mak, Francoise Pierard, Juan-Miguel Jimenez, Jeremy J. Clemens, Sam Sperry, John Studley, Andrew Miller, Dean Stamos, Andreas Termin, Philip N. Collier, Guy Brenchley, Juliana L. Asgian, Brett B. Busch, Jeffrey Abt, Sandra Lechner, Roger Heim, Tina B. Flores, Ray Gross, Dao Tran, Vadims Dvornikovs, Peggy Chiang, Timothy Coon, and Sarah Hudson more...
- Subjects
Metabolite ,Clinical Biochemistry ,Protein Kinase C-epsilon ,Glucuronidation ,Pharmaceutical Science ,Primary alcohol ,Biochemistry ,Kinetic resolution ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Glucuronides ,Pharmacokinetics ,Drug Discovery ,Animals ,Structure–activity relationship ,Protein Kinase Inhibitors ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Metabolism ,Rats ,chemistry ,Molecular Medicine - Abstract
Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed. more...
- Published
- 2014
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