Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain

Wu, Yong‐Jin; Conway, Charles M.; Sun, Li‐Qiang; Machet, Frederic; Chen, Jie; Chen, Ping; He, Huan; Bourin, Clotilde; Calandra, Vincenzo; Polino, Joseph; Davis, Carl D.; Heman, Karen L.; Gribkoff, Valentin K.; Boissard, Christopher G.; Knox, Ronald J.; Thompson, Mark; Fitzpatrick, William; Weaver, David T.; Harden, David G.; Natale, Joanne; Dworetzky, Steven I.; Starrett, John E.

doi:10.1016/j.bmcl.2013.08.092

Cited by 11 publications

(8 citation statements)

References 15 publications

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Section: Channel Openersmentioning

confidence: 99%

“…Other M channel openers include acrylamides known as compounds (S)‐1 and (S)‐2 (Wu et al, ,b,c, ; L'Heureux et al, ) developed by Bristol‐Myers Squibb. Acrylamides share the site of action and specificity profile with retigabine (Bentzen et al, ) and display analgesic efficacy in rodent models of migraine (Wu et al, ), inflammatory and neuropathic pain (Wu et al, ). A QO series of openers is based on pyrazolo[1,5‐a]pyrimidin‐7(4H)‐one (Jia et al, ; Qi et al, ; Zhang et al, ; Teng et al, ); the lead compound, QO‐58 (and QO‐58‐lysine, which has improved bioavailability), has analgesic efficacy in neuropathic and inflammatory pain models (Zhang et al, ; Teng et al, ).…”

Section: Channel Openersmentioning

confidence: 99%

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M‐type K⁺ channels in peripheral nociceptive pathways

Gao

Jaffe

et al. 2017

British J Pharmacology

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Pathological pain is a hyperexcitability disorder. Since the excitability of a neuron is set and controlled by a complement of ion channels it expresses, in order to understand and treat pain, we need to develop a mechanistic insight into the key ion channels controlling excitability within the mammalian pain pathways and how these ion channels are regulated and modulated in various physiological and pathophysiological settings. In this review, we will discuss the emerging data on the expression in pain pathways, functional role and modulation of a family of voltage‐gated K+ channels called ‘M channels’ (KCNQ, Kv7). M channels are increasingly recognized as important players in controlling pain signalling, especially within the peripheral somatosensory system. We will also discuss the therapeutic potential of M channels as analgesic drug targets.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc/

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Section: Channel Openersmentioning

confidence: 99%

Section: Channel Openersmentioning

confidence: 99%

M‐type K⁺ channels in peripheral nociceptive pathways

Gao

Jaffe

et al. 2017

British J Pharmacology

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“…Compound 123 is an orally bioavailable KCNQ2 opener. [151] Structure-activity relationship studies conducted in the group of 25 cinnamamide derivatives indicated that compounds acting as KCNQ2 openers are characterized by an S absolute configuration at the (1-phenyl)ethyl moiety,t he a,b-unsaturated acrylamide functionality with one unsubstituted hydrogen in amide group. )-ana nimal model of prodromal syndrome in migraine.…”

Section: K V 7v Oltage-gated Potassium Channel Activatorsmentioning

confidence: 99%

“…[150] 2-Pyridyloxy substitution on the phenyl ring of the amide moiety resulted in 127,w hichn ot only proved the most efficaciousa s aK CNQ2 openeri nv itro but also showed activity in the Chung model of peripheral neuropathy in rats;t he R enantiomer of 127 was inactive in both assays. [151] Structure-activity relationship studies conducted in the group of 25 cinnamamide derivatives indicated that compounds acting as KCNQ2 openers are characterized by an S absolute configuration at the (1-phenyl)ethyl moiety,t he a,b-unsaturated acrylamide functionality with one unsubstituted hydrogen in amide group. [152]…”

Section: K V 7v Oltage-gated Potassium Channel Activatorsmentioning

confidence: 99%

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Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships

et al. 2015

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The cinnamamide scaffold has been incorporated in to the structure of numerous organic compounds with therapeutic potential. The scaffold enables multiple interactions, such as hydrophobic, dipolar, and hydrogen bonding, with important molecular targets. Additionally, the scaffold has multiple substitution options providing the opportunity to optimize and modify the pharmacological activity of the derivatives. In particular, cinnamamide derivatives have exhibited therapeutic potential in animal models of both central and peripheral nervous system disorders. Some have undergone clinical trials and were introduced on to the pharmaceutical market. The diverse activities observed in the nervous system included anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative properties. Over the last decade, research has focused on the molecular mechanisms of action of these derivatives, and the data reported in the literature include targeting the γ-aminobutyric acid type A (GABAA ) receptors, N-methyl-D-aspartate (NMDA) receptors, transient receptor potential (TRP) cation channels, voltage-gated potassium channels, histone deacetylases (HDACs), prostanoid receptors, opioid receptors, and histamine H3 receptors. Here, the literature data from reports evaluating cinnamic acid amide derivatives for activity in target-based or phenotypic assays, both in vivo and in vitro, relevant to disorders of the central and peripheral nervous systems are analyzed and structure-activity relationships discussed.

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TET1 Participates in Complete Freund’s Adjuvant-induced Trigeminal Inflammatory Pain by Regulating Kv7.2 in a Mouse Model

Zhan,

Zhang,

et al. 2023

Neurosci. Bull.

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Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain

Cited by 11 publications

References 15 publications

M‐type K⁺ channels in peripheral nociceptive pathways

M‐type K⁺ channels in peripheral nociceptive pathways

Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships

TET1 Participates in Complete Freund’s Adjuvant-induced Trigeminal Inflammatory Pain by Regulating Kv7.2 in a Mouse Model

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Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain

Cited by 11 publications

References 15 publications

M‐type K+ channels in peripheral nociceptive pathways

M‐type K+ channels in peripheral nociceptive pathways

Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships

TET1 Participates in Complete Freund’s Adjuvant-induced Trigeminal Inflammatory Pain by Regulating Kv7.2 in a Mouse Model

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Product

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M‐type K⁺ channels in peripheral nociceptive pathways

M‐type K⁺ channels in peripheral nociceptive pathways