6-Substituted 2,2-Bis(fluoromethyl)-benzopyran-4-carboxamide K + channel openers

Taka, Naoki; Koga, Hiroshi; Sato, Haruhiko; Ishizawa, Takenori; Takahashi, Tadakatsu; Imagawa, Jun-ichi

doi:10.1016/s0968-0896(00)00064-x

Cited by 26 publications

(8 citation statements)

References 25 publications

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“…A similar pharmacological profile is described for KC-515 10 with a carboxamide in 4-position and a 6-C 2 F 5 substituent. KC-515 is about 1.5 log units less potent than KC-399 in vitro proving the superiority of thioamide substitution [23]. SAR studies of N-methyl-carbothioamides like 11 do not parallel those of benzopyran KCOs with cyclic 4-substituents [24][25][26].…”

Section: -Positionmentioning

confidence: 95%

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: -Positionmentioning

confidence: 95%

Structure-Activity Relationships of KATP Channel Openers

Mannhold¹

2006

CTMC

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“…These profiles identify (12) as a potential candidate for a new type of antihypertension agents [53]. Almansa et al synthesized a series of 2,2-dialkyltetralin-1-ketone derivatives by replacing the oxygen atom with a carbonyl group, producing by screening UR28225 (7), a compound that constricts and inhibits portal vein and bronchus smooth muscle [47], which are similar to that of compound (1).…”

Section: Benzopyransmentioning

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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“…[1][2][3][4][5][6][7] The incorporation of perfluoroalkyl groups into bioactive molecules often dramatically alters their physical and chemical properties, and biological activities which lead to widespread use of fluorine-containing compounds in the fields of medicinal chemistry [8][9][10]11,12 and material sciences. 13 For instance, pentafluoroethyl groups are featured in many bioactive compounds and drugs, such as the angiotensin II receptor antagonist (DuP 532), 14 antihypertensive K + channel opener (KC-515), 15 perfluoroalkyl substituted aniline insecticides 16 and nucleobases 17 (Scheme 1). The exploration of efficient perfluoroalkylation reactions, is therefore of great urgency.…”

Section: Introductionmentioning

confidence: 99%

A class of effective decarboxylative perfluoroalkylating reagents: [(phen)₂Cu](O₂CR_F)

et al. 2016

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6-Substituted 2,2-Bis(fluoromethyl)-benzopyran-4-carboxamide K + channel openers

Cited by 26 publications

References 25 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

A class of effective decarboxylative perfluoroalkylating reagents: [(phen)₂Cu](O₂CR_F)

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6-Substituted 2,2-Bis(fluoromethyl)-benzopyran-4-carboxamide K + channel openers

Cited by 26 publications

References 25 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

A class of effective decarboxylative perfluoroalkylating reagents: [(phen)2Cu](O2CRF)

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A class of effective decarboxylative perfluoroalkylating reagents: [(phen)₂Cu](O₂CR_F)