Phenoxyphenyl Pyridines as Novel State-Dependent, High-Potency Sodium Channel Inhibitors

Abstract

In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

“…A variety of NaCh reference antagonists, as previously characterized by EP 6,23 or the Na + influx assay, 24 were tested for their ability to inhibit the response to 25 µM veratridine. Inhibition was dependent on compound concentration, except for lidocaine, which exhibited no inhibitory activity up to 66 µM (Fig.…”

“…For some compounds presented in this study, a single concentration was empirically chosen that caused 50% inhibition. 23 From the FR at this concentration, the estimate for K i was obtained using the following equation: …”

Cross‐Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom

“…[182] On the other hand, azine N-oxides 262 were efficiently converted to the corresponding azines by N-oxide deoxygenation through treatment with Pd/C and ammonium formate in methanol at room temperature (Scheme 141). [180] The potential utility of this arylation/deoxygenation protocol was then illustrated by its use in a five-step synthesis of the channel inhibitor 265 [183] (Figure 37) in which compounds 263 and 264 ( Figure 37) were key intermediates. [180] Unfortunately, the protocol used to prepare pyridine N-oxides 262 proved to be unsuitable for the highly site selective C-2 arylation of isoquinoline Noxide (266) with aryl bromides.…”

“…(a), Scheme 142]. [183] Moreover, they determined that 273 underwent sp 3 arylation when the reaction with 4-bromotoluene was carried out under microwave irradiation in the presence of t-BuONa as the base and using a catalyst system composed by 2.5 mol% Pd 2 A C H T U N G T R E N N U N G (dba) 3 and 5 mol% XPhos [Eq. (b), Scheme 142].…”

Dibenzazepines and dibenzoxazepines as sodium channel blockers

“…7,10,11 Previous research in our lab has resulted in several series of sodium channel blockers and culminated with the discovery of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA, 2), a broad-spectrum state-dependent blocker which was efficacious in multiple models of chronic pain. [12][13][14] As part of a broad scaffold hopping strategy toward the discovery of novel chemotypes, we envisioned placing a tether between the A and B-rings of PPPA giving rise to ring constrained compounds such as 4 ( Fig. 1).…”