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.

The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

“…The lack of subtype selectivity of these pharmacological modulators has thus been a substantial limitation for gaining an improved understanding of the K V 7 channel subtypes most critical to DSM function. A novel K V 7 channel activator, ICA-069673, has demonstrated selectivity for heteromeric K V 7.2/K V 7.3 channels and is a pyrimidine analog of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide] Wickenden et al, 2008;Amato et al, 2011). Although it is less potent than its related analog ICA-27243, ICA-069673 displays greater efficacy and improved selectivity for heteromeric K V 7.2/K V 7.3 over K V 7.1 channels (Amato et al, 2011).…”

“…A novel K V 7 channel activator, ICA-069673, has demonstrated selectivity for heteromeric K V 7.2/K V 7.3 channels and is a pyrimidine analog of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide] Wickenden et al, 2008;Amato et al, 2011). Although it is less potent than its related analog ICA-27243, ICA-069673 displays greater efficacy and improved selectivity for heteromeric K V 7.2/K V 7.3 over K V 7.1 channels (Amato et al, 2011). In contrast with retigabine, which binds to the pore region (S5 to S6) of K V 7.2-K V 7.5 channels (Gunthorpe et al, 2012), evidence suggests that ICA-069673 is among an emerging novel class of compounds known as "gating modifiers," named so for their ability to bind to the S1-S4 voltage-sensing domain of K V 7 channels Peretz et al, 2010;Brueggemann et al, 2014a).…”

“…ICA-069673 demonstrated 20-fold greater selectivity for heteromeric K V 7.2/ K V 7.3 channels over K V 7.3/K V 7.5, with EC 50 values of 0.69 and 14.3 mM, respectively (Amato et al, 2011). ICA-069673 did not affect K V 7.1 channels, which are predominately expressed in the heart (Amato et al, 2011).…”

“…ICA-069673 demonstrated 20-fold greater selectivity for heteromeric K V 7.2/ K V 7.3 channels over K V 7.3/K V 7.5, with EC 50 values of 0.69 and 14.3 mM, respectively (Amato et al, 2011). ICA-069673 did not affect K V 7.1 channels, which are predominately expressed in the heart (Amato et al, 2011). A recent study on A7r5 smooth muscle cells demonstrated that ICA-069673 was effective in activating recombinantly expressed K V 7.4 channels (Brueggemann et al, 2014a).…”

“…The novel compound ICA-069673 [N-(2-chloro-5-pyrimidinyl)-3,4-difluorobenzamide] was developed by Icagen, Inc. (Durham, NC) in a screening program to identify subtype-selective K V 7 channel activators (Amato et al, 2011). ICA-069673 demonstrated 20-fold greater selectivity for heteromeric K V 7.2/ K V 7.3 channels over K V 7.3/K V 7.5, with EC 50 values of 0.69 and 14.3 mM, respectively (Amato et al, 2011).…”