Synthesis and evaluation of (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones as Kv1.5 channel blockers for the treatment of atrial fibrillation

Blass, Benjamin E.; Coburn, Keith R.; Lee, Wenlin; Fairweather, Neil; Fluxe, Andrew; Wu, Shengde; Janusz, John M.; Murawsky, Michael; Fadayel, Gina; Fang, Bin; Hare, Michelle; Ridgeway, J. M.; White, Ron; Jackson, C. M.; Djandjighian, Laurent; Hedges, Richard M.; Wireko, F. C.; Ritter, Amanda

doi:10.1016/j.bmcl.2006.06.001

Cited by 33 publications

(28 citation statements)

References 10 publications

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“…[164] A unchanged. [165] A group of sulfonylamino-substituted imidazolidinones 45 as potent Kv1. AF burden (total time in AF) decreased 52%.…”

Section: Ortho-disubstituted Bisaryl Compoundsmentioning

confidence: 99%

Linked biaromatic compounds as cardioprotective agents

Mokrov

2021

Archiv der Pharmazie

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Cardiovascular diseases (CVDs) are widespread in the modern world, and their number is constantly growing. For a long time, CVDs have been the leading cause of morbidity and mortality worldwide. Drugs for the treatment of CVD have been developed almost since the beginning of the 20th century, and a large number of effective cardioprotective agents of various classes have been created. Nevertheless, the need for the design and development of new safe drugs for the treatment of CVD remains. Literature data indicate that a huge number of cardioprotective agents of various generations and mechanisms correspond to a single generalized pharmacophore model containing two aromatic nuclei linked by a linear linker. In this regard, we put forward a concept for the design of a new generation of cardioprotective agents with a multitarget mechanism of action within the indicated pharmacophore model. This review is devoted to a generalization of the currently known compounds with cardioprotective properties and corresponding to the pharmacophore model of biaromatic compounds linked by a linear linker. Particular attention is paid to the history of the creation of these drugs, approaches to their design, and analysis of the structure-action relationship within each class.

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“…[164] A unchanged. [165] A group of sulfonylamino-substituted imidazolidinones 45 as potent Kv1. AF burden (total time in AF) decreased 52%.…”

Section: Ortho-disubstituted Bisaryl Compoundsmentioning

confidence: 99%

Linked biaromatic compounds as cardioprotective agents

Mokrov

2021

Archiv der Pharmazie

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“…In recent years, there have been many novel types of K v 1.5 channel blockers reported that differ from traditional anti-arrhythmic agents. These K v 1.5 channel blockers include AVE0118, [14] S-0100176, [15] ISQ-1, [16] TAEA, [17] ICA-32 and analogues, [18][19][20] BMS34136, [21] as well as some benzopyran sulfonamide derivatives such as NIP-142. [22] FurtherAtrial fibrillation (AF) is the most prevalent nonfatal cardiac rhythm disorder associated with an increased risk of heart failure and stroke.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of K_v1.5 Channel Blockers

Yang

Fedida

et al. 2010

ChemMedChem

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Atrial fibrillation (AF) is the most prevalent nonfatal cardiac rhythm disorder associated with an increased risk of heart failure and stroke. Considering the ventricular side effects induced by anti-arrhythmic agents in current use, K(v)1.5 channel blockers have attracted a great deal of deliberation owing to their selective actions on atrial electrophysiology. Herein we report new chemotypes of K(v)1.5 channel blockers that were identified through a combination of structure-based virtual screening and in silico druglike property prediction including six scoring functions, as well as electrophysiological evaluation. Among them, five of the 18 compounds exhibited >50 % blockade ratio at 10 microM, and have structural features different from conventional K(v)1.5 channel blockers. These novel scaffolds could serve as hits for further optimization and SAR studies for the discovery of selective agents to treat AF.

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“…Common synthetic approaches to 4-substituted 1 H -1,2,3-triazoles involve a [3+2] cycloaddition between sodium azide (NaN 3 ) or hydrazoic acid (HN 3 ) and terminal alkynes activated with electron-withdrawing groups (EWGs) (Hartzel and Benson, 1954; Balle et al, 2003; Blass et al, 2006; Koszytkowska-Stawińska et al, 2012). A variation of this classical methodology using trimethylsilyl azide (TMSN 3 ) provides a much safer procedure.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Tris-Heterocycles via a Cascade IMCR/Aza Diels-Alder + CuAAC Strategy

et al. 2019

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6-Triazolylmethyl-pyrrolo[3,4- b ]pyridin-5-one tris-heterocycles were synthesized in 43–57% overall yields. The two-stage synthesis involved a cascade process (Ugi-3CR/aza Diels-Alder/ N -acylation/aromatization) followed by a copper-assisted alkyne-azide [3+2] cycloaddition (CuAAC). This efficient and convergent strategy proceeded via complex terminal alkynes functionalized with a fused bis-heterocycle at the α-position. The final products are ideal candidates for SAR studies as they possess two privileged scaffolds in medicinal chemistry: 4-substituted or 1,4-substituted 1 H -1,2,3-triazoles and pyrrolo[3,4- b ]pyridin-5-ones.

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Synthesis and evaluation of (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones as Kv1.5 channel blockers for the treatment of atrial fibrillation

Cited by 33 publications

References 10 publications

Linked biaromatic compounds as cardioprotective agents

Linked biaromatic compounds as cardioprotective agents

Structure‐Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of K_v1.5 Channel Blockers

Synthesis of Tris-Heterocycles via a Cascade IMCR/Aza Diels-Alder + CuAAC Strategy

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Synthesis and evaluation of (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones as Kv1.5 channel blockers for the treatment of atrial fibrillation

Cited by 33 publications

References 10 publications

Linked biaromatic compounds as cardioprotective agents

Linked biaromatic compounds as cardioprotective agents

Structure‐Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of Kv1.5 Channel Blockers

Synthesis of Tris-Heterocycles via a Cascade IMCR/Aza Diels-Alder + CuAAC Strategy

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Structure‐Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of K_v1.5 Channel Blockers