N-Pyridyl and Pyrimidine Benzamides as KCNQ2/Q3 Potassium Channel Openers for the Treatment of Epilepsy

  • ACS Med Chem Lett. 2011 Mar 31;2(6):481-4. doi: 10.1021/ml200053x.
George Amato  1 ,  Rosemarie Roeloffs  1 ,  Greg C Rigdon  1 ,  Brett Antonio  1 ,  Theresa Mersch  1 ,  Grant McNaughton-Smith  1 ,  Alan D Wickenden  1 ,  Paul Fritch  1 ,  Mark J Suto  1
Affiliations
  • 1. Departments of Chemistry, Pharmacology, and Biology, Icagen Inc. , 4222 Emperor Boulevard, Durham, North Carolina 27702, United States.
PMID: 24900334 DOI: 10.1021/ml200053x
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.

Keywords
KCNQ2/Q3; Potassium channel; epilepsy.
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