Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic K_V7 channel openers: Exploration of a nicotinamide scaffold

Abstract

K V 7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued K V 7 channel openers flupirtine and retigabine bear an oxidation-sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine. Optimization of a nicotinamide lead structure yielded analogs with excellent K V 7.2/3 opening activity, as evidenced by EC 50 values approaching the single-digit nanomolar range. On the other hand, weighted K V 7.2/3 opening activity data including inactive compounds allowed for the establishment of structure-activity relationships and a plausible binding mode hypothesis verified by docking and molecular dynamics simulations.channels are homo-or heterotetrameric, voltage-gated potassium channels expressed in various tissues, [1] whereby especially heterotetrameric neuronal K V 7 channels predominantly composed of K V 7.2 and K V 7.3 subunits are validated pharmacological targets. [2] In general, K V 7 activation induces hyperpolarization of cell membranes, through which the ion channels contribute to controlling neuronal excitability. By increasing the action potential threshold [3] and medium afterhyperpolarization while reducing spike frequency, [4] K V 7 channels act as a "brake" for hyperexcitability. [5] Moreover, their opening probability can be influenced by small-molecule ligands, [6] making them attractive therapeutic targets, particularly for a range of neurological diseases. [5] For example, the administration of K V 7 channel openers was recently discussed for the therapy of various forms of brain damage, including chronic stress-induced brain injury (CSBI) as well as traumatic brain injury (TBI), for which currently no pharmacotherapeutic treatment options exist. In both cases, animal models suggest that reducing the underlying neuronal hyperexcitability by enhancing K V 7-mediated potassium currents might offer a protective effect. Thus, K V 7 channel activation may be a novel therapeutic intervention

A graphite furnace‐atomic absorption spectrometry‐based rubidium efflux assay for screening activators of the Kv7.2/3 channel

“…Therefore, in the case of transferring this assay for the investigation of other cells (expressing other potassium channels, such as the K v 7. house library [21][22][23] were selected for investigation in the current study.…”

“…: 4ti‐0221). A total of 16 compounds from the in‐house library [ 21–23 ] were selected for investigation in the current study. Ultrapure water obtained from an ELGA Purelab flex system (Veolia) was used throughout the experiments.…”

“…For all other compounds tested, the LogD 7.4 ranged from value 2.3−3.8. [21][22][23] Consequently, poor water solubility could lead to the precipitation of compound 10 in the aqueous medium, so its channel-opening properties could not be properly determined in the Rb efflux assay. This assumption is also supported by the results from the FLIPR potassium assay.…”

In Silico Methods for the Discovery of Kv7.2/7.3 Channels Modulators: A Comprehensive Review

“…In summary, metabolic instable triaminoaryl structure was to a nicotinamide scaffold thus paving the way for the development of a novel class of potential Kv7 activators. [48,58] From the work of Wurm et al, it emerges that moving to nicotinamide core, additional structural modification are requested to maintain a Kv7.2/7.3 opening activity, e.g. the introduction of an additional benzylic amide side chain together with a methyl group on pyridine core as in compound 25.…”

Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine

“…Therefore, the above adverse events of retigabine seem to originate from its chemical structure but not from the KCNQ2 target [ 8 ]. Accordingly, great efforts are made to search for new KCNQ2 agonists for AED candidates based on the optimization of retigabine structure [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”