title: Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.
abstract: We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Pengcheng P
authors.initials: PP
authors.lastname: Shao
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Ye
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Chakravarty
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Herrington
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ge
authors.initials: G
authors.lastname: Dai
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Randal M
authors.initials: RM
authors.lastname: Bugianesi
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Rodolfo J
authors.initials: RJ
authors.lastname: Haedo
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swensen
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Vivien A
authors.initials: VA
authors.lastname: Warren
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: McHardy M
authors.initials: MM
authors.lastname: Smith
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Owen B
authors.initials: OB
authors.lastname: McManus
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Green
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Jochnowitz
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: McGowan
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Mistry
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Sun
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Abbadie
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.affiliation: Departments of Medicinal Chemistry, Ion Channels, Drug Metabolism and Pharmacokinetics, and Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
keywords: Cav2.2; N-type calcium channel; bioisostere; pain; sulfonamide; sulfone