Synthesis and pharmacological evaluation of 4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide and N-(2-cyanomethylsulfonylphenyl)acylamide derivatives as potential activators of ATP sensitive potassium channels

Schou, Søren Christian; Hansen, Holger C.; Tagmose, Tina M.; Boonen, Harrie C. M.; Worsaae, Anne; Drabowski, Michael; Wahl, Philip; Arkhammar, Per; Bödvarsdóttir, Thóra B.; Antoine, Marie-Hélène; Lebrun, Philippe; Hansen, John Bondo

doi:10.1016/j.bmc.2004.09.051

Cited by 29 publications

(13 citation statements)

References 27 publications

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“…To further explore the SAR of thiadiazine KCOs, Schou et al [75] synthesized and evaluated structural variations of the thiadiazine moiety resulting in 4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxides such as 54 and N-(2-cyanomethylsulfonylphenyl)acylamide derivatives such as 55. KCO activity is retained with both types of variation.…”

Section: Prototypementioning

confidence: 99%

Structure-Activity Relationships of KATP Channel Openers

Mannhold¹

2006

CTMC

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Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs) e.g. relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. Structure-activity relationships of the main chemical classes of KCOs are discussed.

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Section: Prototypementioning

confidence: 99%

Structure-Activity Relationships of KATP Channel Openers

Mannhold¹

2006

CTMC

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“…Schou et al performed a series of structural modifications by introducing the lateral chain and ring cleavage on the mother nucleus of diazoxide to obtain a series of KCOs with high selectivity [76] Fig. (14).…”

Section: Diazoxide and Pinacidil Derivativesmentioning

confidence: 99%

ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine Derivatives

Wang¹,

Tang²,

Wang³

et al. 2007

CMC

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ATP-sensitive potassium (K(ATP)) channels have important functions through their coupling of cellular energetic networks and their ability to decode metabolic signals, and they are implicated in diseases of many organs. K(ATP) channels are formed by the physical association between the inwardly rectifier potassium channels (Kir6.x) and the regulatory sulfonylurea receptor subunit (SUR), which form a hetero-octameric complex. Different subtypes of K(ATP) channels exist in various tissues. K(ATP) channel openers (KCOs) are classified into nine chemical families according to their molecular structures: (1) benzopyrans, (2) cyanoguanidines, (3) thioformamides, (4) pyrimidine derivatives, (5) pyridine derivatives, (6) benzothiadiazines, (7) dihydropyridines, (8) nicotinamide derivatives, and (9) aliphatic amines. Although the model also predicts that KCOs have four co-binding areas, it was hypothesized that the main contribution lies in the binding domain of hydrophobicity of the side chain. A series of compounds containing the skeleton of the aliphatic secondary amines as a side chain was designed. It was found that N-isopropyl 2,3-dimethyl-2-butylamine (iptakalim, 91) is a novel KCOs. Iptakalim regulates the pore selectively of the inwardly rectifier potassium channel and dilates smaller arteries, but has little effect on vasodilatation of the aorta. Iptakalim administered p.o. has selective and long-lasting antihypertensive effects in hypertensive animals and does not induce tolerance, but has little effect on blood pressure in normotensive animals. Meanwhile, it also reverses cardiovascular remodeling and protects the brain and kidney against damage caused by hypertension in animal models. Iptakalim is in phase II clinical trials now and has a promising future as a treatment for hypertension.

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“…N-4 Functionalization with cyclopeantenone moiety was achieved by reaction of key intermediates 132-134 with the crude product obtained by reacting cyclopentanone and NBS in the presence of a catalytic amount of dibenzoyl peroxide. 1,4-Benzothiazine 1,1-dioxide 72 [110] was instead synthesized by base-catalyzed ring closure of cyanomethylsulfone 137 (Scheme 16). This, in turn, was prepared from pyridinium sulfonate 135 [125] by conversion into the unstable sulfonyl chloride, reduction to sulfinic acid 136 via Lee and Field procedure [126], followed by cyanomethylation.…”

Section: 4-benzothiazinesmentioning

confidence: 99%

From Cromakalim to Different Structural Classes of KATP Channel Openers

Cecchetti¹,

Tabarrini²,

Sabatini³

2006

CTMC

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ATP-Sensitive potassium channel openers (K(ATP)COs) are a group of compounds with a broad spectrum of potential therapeutic applications, as they constitute efficient tools for dampening cell excitability. Interest in the K(ATP)COs was triggered in the early 1980s by the discovery of the benzopyran-based structure cromakalim (CRK), which is a powerful smooth muscle relaxant. CRK can be considered the archetype of K(ATP)COs and is by far the most mimicked structure. In many structure-activity studies various substitutions have been made at the different positions of the benzopyran ring permitting the optimal activity to be correlated with a specific set of structural characteristics and stereochemical features of the molecule. Thus, many potent benzopyran derivatives have been identified. The benzopyran nucleus itself has also been modified in both the aromatic ring and in the pyran moiety. The intention of this review is to bring together all the different structural classes of K(ATP)COs arising from the replacement of CRK benzopyran-based structure with various ring systems; design, structure-activity relationship, and synthesis will be given.

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Synthesis and pharmacological evaluation of 4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide and N-(2-cyanomethylsulfonylphenyl)acylamide derivatives as potential activators of ATP sensitive potassium channels

Cited by 29 publications

References 27 publications

Structure-Activity Relationships of KATP Channel Openers

Structure-Activity Relationships of KATP Channel Openers

ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine Derivatives

From Cromakalim to Different Structural Classes of KATP Channel Openers

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