Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers: WO2010066840

Wulff, Heike

doi:10.1517/13543776.2010.528392

Cited by 9 publications

(4 citation statements)

References 59 publications

(59 reference statements)

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“…PAP‐1, a synthesized compound Kv1.3 selective, suppresses allergic contact dermatitis by reducing IFN‐ γ production from T EM cells . The synthesized spiro azepone‐oxazolidinone is also considered a novel blocker of Kv1.3 channel for the treatment of diabetes, psoriasis, obesity, transplant rejection and T‐cell mediated autoimmune diseases …”

Section: Discussionmentioning

confidence: 99%

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Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

et al. 2016

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SummaryThe voltage-gated potassium channel Kv1.3 is a novel target for immunomodulation of autoreactive effector memory T cells, which play a major role in the pathogenesis of autoimmune diseases. In this study, the Ts6 and Ts15 toxins isolated from Tityus serrulatus (Ts) were investigated for their immunosuppressant roles on CD4 + cell subsets: naive, effector (T EF ), central memory (T CM ) and effector memory (T EM ). The electrophysiological assays confirmed that both toxins were able to block Kv1.3 channels. Interestingly, an extended Kv channel screening shows that Ts15 blocks Kv2.1 channels. Ts6 and Ts15 significantly inhibit the proliferation of T EM cells and interferon-c production; however, Ts15 also inhibits other CD4 + cell subsets (naive, T EF and T CM ). Based on the Ts15 inhibitory effect of proliferation of all CD4 + cell subsets, and based on its blocking effect on Kv2.1, we investigated the Kv2.1 expression in T cells. The assays showed that CD4 + and CD8 + cells express the Kv2.1 channels mainly extracellularly with T CM cells expressing the highest number of Kv2.1 channels. We also provide in vivo experimental evidence to the protective effect of Ts6 and Ts15 on delayed-type hypersensitivity reaction. Altogether, this study presents the immunosuppressive behaviour of Ts6 and Ts15 toxins, indicating that these toxins could be promising candidates for autoimmune disease therapy. Moreover, this is the first report illustrating the involvement of a novel K + channel subtype, Kv2.1, and its distribution in T-cell subsets.

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Section: Discussionmentioning

confidence: 99%

“…Recently, many important studies have shown that the T EM is associated with autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, lupus systemic erythematosus and type II diabetes) and that the Kv1.3 channel is up‐regulated in these cells …”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

et al. 2016

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“…Derivatives of correolide, a pentacyclic natural compound, have been the object of a SAR study [177]. Patent applications seek to protect whole classes of synthetic K V 1.3 blockers, based on an amide [178] or an oxazolidinedione [179] core. Interestingly, PM K V 1.3 is inhibited downstream of ceramide production by acid sphingomyelinase (ASM) [180].…”

Section: Mitochondrial K V Channelsmentioning

confidence: 99%

Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents

Parrasia

Mattarei

Furlan

et al. 2019

Cell Physiol Biochem

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“…There are also a number of small compounds that modulate the K V 1.3 channel by binding either to the inner pore, the gating‐hinges or the interface between the α‐ and β‐subunit, in contrast to peptide toxins, which affect K V channel from the extracellular side. Small molecule K V 1.3 blockers such as PAP‐1 ( 1 ), a psoralen natural product derivative, (IC 50 =2 nM), nor ‐triterpene correolide ( 2 ), a natural product isolated from the tree Spachea correa , (IC 50 =90 nM), CP‐339818 ( 3 ), a dihydroquinolone derivative, (IC 50 =200 nM), UK‐78282 ( 4 ), a piperidine derivative, (IC 50 =200 nM), PAC ( 5 ), a benzamide derivative, (IC 50 =260 nM), 4‐( p ‐chlorobenzyloxy)‐khellinone ( 6 ), a natural product derivative, (IC 50 =400 nM), and clofazimine ( 7 ), a FDA‐approved drug for leprosy, (IC 50 =300 nM) have been reported, Figure .…”

Section: Introductionmentioning

confidence: 99%

A Ligand‐Based Approach to the Discovery of Lead‐Like Potassium Channel K_V1.3 Inhibitors

et al. 2018

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Voltage‐gated ion channels are key molecular targets for autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and psoriasis. In silico models, using 340 molecules whose IC50 towards Kv1.3 was determined by reported assays, were developed through exploration of four machine learning (ML) techniques. ML techniques explored included Random Forest, Support Vector Machine, Multilayer Perceptron, and K‐Nearest Neighbors. Two QSAR classification approaches were developed. In the first approach, the compounds were classified into either moderate‐active‐to‐very‐active or inactive‐to‐moderate‐active categories. Only the compounds predicted to be moderate‐active‐to‐very‐active in the first classification model were submitted to the second model, a classification model that predicted two more categories, very‐active and not‐very‐active. The performances of the models were successfully evaluated by internal validation and external test set validation, with an overall predictability (Q) of 0.83 and 0.69 for the test set in the first and second approaches of the best models, respectively. The best models for the two approaches were employed for the virtual screening of KV1.3 inhibitors from ZINC natural products and approved drugs databases. A list of the most promising lead‐like KV1.3 inhibitors was proposed, from which an approved drug and a natural product were experimentally evaluated with whole‐cell voltage‐clamp assays at 1000 nM.

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Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers: WO2010066840

Cited by 9 publications

References 59 publications

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents

A Ligand‐Based Approach to the Discovery of Lead‐Like Potassium Channel K_V1.3 Inhibitors

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Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers: WO2010066840

Cited by 9 publications

References 59 publications

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K+ channel pattern in T cells

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K+ channel pattern in T cells

Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents

A Ligand‐Based Approach to the Discovery of Lead‐Like Potassium Channel KV1.3 Inhibitors

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Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K⁺ channel pattern in T cells

A Ligand‐Based Approach to the Discovery of Lead‐Like Potassium Channel K_V1.3 Inhibitors