title: Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors.
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.
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: jeremy_clemens@vrtx.com.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Clemens
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Coon
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Brett B
authors.initials: BB
authors.lastname: Busch
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Juliana L
authors.initials: JL
authors.lastname: Asgian
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hudson
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Termin
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Tina B
authors.initials: TB
authors.lastname: Flores
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Dao
authors.initials: D
authors.lastname: Tran
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Peggy
authors.initials: P
authors.lastname: Chiang
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Sam
authors.initials: S
authors.lastname: Sperry
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Ray
authors.initials: R
authors.lastname: Gross
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Abt
authors.affiliation: Department of Biology, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Roger
authors.initials: R
authors.lastname: Heim
authors.affiliation: Department of Biology, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lechner
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom.
authors.forename: Heather
authors.initials: H
authors.lastname: Twin
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Studley
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom.
authors.forename: Guy
authors.initials: G
authors.lastname: Brenchley
authors.affiliation: Department of Medicinal Chemistry, Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Collier
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom.
authors.forename: Francoise
authors.initials: F
authors.lastname: Pierard
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom.
authors.forename: Chau
authors.initials: C
authors.lastname: Mak
authors.affiliation: Department of Medicinal Chemistry, Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Vadims
authors.initials: V
authors.lastname: Dvornikovs
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom.
authors.forename: Juan-Miguel
authors.initials: JM
authors.lastname: Jimenez
authors.affiliation: Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D020719:Glucuronides; D047428:Protein Kinase Inhibitors; D051744:Protein Kinase C-epsilon
keywords: Glucuronidation; Metabolism; PKCε; Phase II; Polarity