title: N-Pyridyl and Pyrimidine Benzamides as KCNQ2/Q3 Potassium Channel Openers for the Treatment of Epilepsy.
abstract: A series of N-pyridyl benzamide KCNQ2/Q3 potassium channel openers were identified and found to be active in animal models of epilepsy and pain. The best compound 12 [ICA-027243, N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide] has an EC50 of 0.38 μM and is selective for KCNQ2/Q3 channels. This compound was active in several rodent models of epilepsy and pain but upon repeated dosing had a number of unacceptable toxicities that prevented further development. On the basis of the structure-activity relationships developed around 12, a second compound, 51, [N-(2-chloro-pyrimidin-5-yl)-3,4-difluoro-benzamide, ICA-069673], was prepared and advanced into a phase 1 clinical study. Herein, we describe the structure-activity relationships that led to the identification of compound 12 and to the corresponding pyrimidine 51.
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: George
authors.initials: G
authors.lastname: Amato
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Roeloffs
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Greg C
authors.initials: GC
authors.lastname: Rigdon
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Brett
authors.initials: B
authors.lastname: Antonio
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Theresa
authors.initials: T
authors.lastname: Mersch
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Grant
authors.initials: G
authors.lastname: McNaughton-Smith
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Fritch
authors.affiliation: Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Suto
keywords: KCNQ2/Q3; Potassium channel; epilepsy