Inhibitors of potassium channels KV1.3 and IK-1 as immunosuppressants

Pegoraro, Stefano; Lang, Martin; Dreker, Tobias; Kraus, Jürgen; Hamm, Svetlana; Meere, Cathal; Feurle, Juliane; Tasler, Stefan; Prütting, Sylvia; Kuras, Zerrin; Visan, Violeta; Grissmer, Stephan

doi:10.1016/j.bmcl.2009.02.077

Cited by 49 publications

(34 citation statements)

References 31 publications

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“…In 2009, Pegaro et al reported the discovery of two structurally new classes of Kv1.3 and KCa3.1 inhibitors based on a virtual high throughput screening approach [84]. A homology model of the Kv1.3 channel was created from the crystal structure of the bacterial KcsA channel and used for a virtual screen of around 3.3 million compounds.…”

Section: Small Molecule Kv13 Blockersmentioning

confidence: 99%

Use of Kv1.3 Blockers for Inflammatory Skin Conditions

Nguyen

Howard

Neale

et al. 2010

CMC

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Recent results using animal models of inflammatory skin conditions have shown that blockers of the voltage-gated potassium channel, Kv1.3 hold great promise for clinical utility. Kv1.3 blockers act as immunosuppressants by modulating the various subsets of inflammatory T and B cells involved in autoimmune disorders. While peptidic inhibitors based on naturally occurring venoms demonstrate potent and selective Kv1.3 blockade, these require parenteral administration and may face potential immunogenicity problems. Small molecule blockers show considerable diversity, however selectivity over other Kv1- family channels has been difficult to achieve. More recent advances have added to the evidence that Kv1.3 channels are a suitable therapeutic target and that the development of novel and selective agents will herald new drugs for inflammatory skin disorders.

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Section: Small Molecule Kv13 Blockersmentioning

confidence: 99%

Use of Kv1.3 Blockers for Inflammatory Skin Conditions

Nguyen

Howard

Neale

et al. 2010

CMC

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“…Thecatalytic cycle is initiated with an amino-assisted CÀHb ond cleavage of 1a by Pd-(OAc) 2 to give rise to as table palladacycle (4). Next, this dimeric palladium complex is broken into its component parts by 2 to form the intermediate I.N otably,i tw as known from prior work that migratory insertion of the alkyne 2 with 4 favored ar egioselective insertion into the PdÀCb ond to afford the eight-membered intermediate II.…”

Section: Methodsmentioning

confidence: 98%

“…[2] Functionalized dibenzo [b,d]azepines were also investigated as serotonin (5-HT) receptor [3] and potassium channel inhibitor. [4] Therefore, the search for new reliable synthetic approaches for the preparation of dibenzo [b,d]azepines from readily available starting materials is of great interest.…”

mentioning

confidence: 99%

Highly Stereoselective Synthesis of Imine‐Containing Dibenzo[b,d]azepines by a Palladium(II)‐Catalyzed [5+2] Oxidative Annulation of o‐Arylanilines with Alkynes

et al. 2015

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An ovel palladium(II)-catalyzed [5+ +2] oxidative annulation of readily available o-arylanilines with alkynes has been developed for building aseven-membered N-heterocyclic architecture containing ab iaryl linkage.T his method is applicable to aw ide range of unprotected o-arylanilines and internal alkynes,and results in the chemoselective preparation of imine-containing dibenzo [b,d]azepines in high yields with excellent diastereoselectivity with respect to the two types of stereogenic elements.Dibenzo [b,d]azepines represent an important class of medium-sized N-heterocycles because they are the key structural motifs in many natural products and bioactive compounds ( Figure 1). Forexample,dimeric erythrivarine B, which contains the seven-membered skeleton, was isolated from cultivated E. variegata.[1] LY-411575 was identified as an effective g-secretase inhibitor for the treatment of melanoma and Alzheimers disease. [2] Functionalized dibenzo [b,d]azepines were also investigated as serotonin (5-HT) receptor [3] and potassium channel inhibitor.[4] Therefore, the search for new reliable synthetic approaches for the preparation of dibenzo [b,d]azepines from readily available starting materials is of great interest.Recently,t ransition-metal-catalyzed C À Hf unctionalization has emerged as an efficient and versatile method for accessing various heterocycles and carbocycles.[5] In particular, nitrogen-group-assisted heteroannulations of nitrogencontaining coupling partners with alkynes by aC À Hcleavage/ alkyne insertion/cyclization cascade have been widely used to generate structurally diverse N-heterocyclic compounds,such as indoles, [6] pyrroles, [7] isoquinolines, [8] isoquinolinones, [9] and so on.[10] Remarkably,m ost of these transformations were realized by formal [3+ +2] or [4+ +2] cycloadditions to give fiveor six-membered rings,but the construction of larger rings by means of related annulations is quite rare. [10c,e] In this context, we set out to develop anew type of [5+ +2] annulation between simple biaryl precursors and alkynes involving aC À H activation step for the synthesis of functionalized dibenzo-[b,d]azepines. [11] This work originated from our recent studies on ruthenium(II)-catalyzed oxidative annulation of o-arylphenol derivatives with alkynes through aC À Ha ctivation strategy (Scheme 1a).[12] It is noteworthy that the reaction proceeded exclusively by ad earomatizing [3+ +2] annulation pathway to generate spirocyclic enones as the sole product, but not dibenzoxepines through apossible [5+ +2] cycloaddition route. Presumably,aclear steric clash between the two twisted aromatic groups of the intermediate A played ak ey role in driving the essential ring contraction from A to B,t hus hampering the reductive elimination of A to form adibenzoxepine and rendering the [3+ +2] spiroannulation more favorable than as even-membered ring formation. Moreover, ar ecent seminal report from the group of MascareÇas and Gulías demonstrated that simple o-vinylphenols (R = H), which cannot enga...

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“…Finally, potassium channels are attractive targets for drug discovery because of its implication in essential processes in biological systems. Pegoraro et al [115] identified blockers of Kv1.3 potassium channels using a KcsA template for homology modeling, and a virtual screening approach. The new compounds displayed inhibitory effects on T-cell and keratinocytes proliferation and immunosuppressant activity.…”

Section: Structure-based Methods Docking Virtual Screening and Molementioning

confidence: 99%

Ionic Channels as Targets for Drug Design: A Review on Computational Methods

et al. 2011

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Ion channels are involved in a broad range of physiological and pathological processes. The implications of ion channels in a variety of diseases, including diabetes, epilepsy, hypertension, cancer and even chronic pain, have signaled them as pivotal drug targets. Thus far, drugs targeting ion channels were developed without detailed knowledge of the molecular interactions between the lead compounds and the target channels. In recent years, however, the emergence of high-resolution structures for a plethora of ion channels paves the way for computer-assisted drug design. Currently, available functional and structural data provide an attractive platform to generate models that combine substrate-based and protein-based approaches. In silico approaches include homology modeling, quantitative structure-activity relationships, virtual ligand screening, similarity and pharmacophore searching, data mining, and data analysis tools. These strategies have been frequently used in the discovery and optimization of novel molecules with enhanced affinity and specificity for the selected therapeutic targets. In this review we summarize recent applications of in silico methods that are being used for the development of ion channel drugs.

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Inhibitors of potassium channels KV1.3 and IK-1 as immunosuppressants

Cited by 49 publications

References 31 publications

Use of Kv1.3 Blockers for Inflammatory Skin Conditions

Use of Kv1.3 Blockers for Inflammatory Skin Conditions

Highly Stereoselective Synthesis of Imine‐Containing Dibenzo[b,d]azepines by a Palladium(II)‐Catalyzed [5+2] Oxidative Annulation of o‐Arylanilines with Alkynes

Ionic Channels as Targets for Drug Design: A Review on Computational Methods

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