The design of a novel class of potassium channel activating drugs, 2-(2,2-dimethylbenzopyran-4-yl)-pyridine-1-oxides

Attwood,; Jones, PS; Kay, PB; Paciorek, P.M.; Redshaw, Sally

doi:10.1016/0024-3205(91)90096-t

Cited by 21 publications

(6 citation statements)

References 8 publications

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“…In the modifications carried out at the C-2 position, the removal of one or both methyl groups (compounds 2 and 3 , respectively) caused a progressive reduction of the vasorelaxant potency. These findings are in agreement with those already reported for the KCO benzopyran class, , confirming a primary role played by the C-2 gem -dimethyl group in obtaining highly active compounds. A reduction in potency was also observed when the gem -dimethyl group was shifted from the C-2 to the C-3 position (compound 4 ).…”

Section: Resultssupporting

confidence: 93%

1,4-Benzothiazine ATP-Sensitive Potassium Channel Openers: Modifications at the C-2 and C-6 Positions

et al. 2013

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ATP-sensitive potassium (KATP) channels play a prominent role in controlling cardiovascular function. In this paper, a novel series of 4-(1-oxo-2-cyclopentenyl)-1,4-benzothiazine derivatives modified at the C-2, and C-6 positions were synthesized as openers of vascular KATP channels. Most of the tested compounds evoked vasorelaxing effects on rat aortic rings and membrane hyperpolarization in human vascular smooth muscle cells, with potency similar or superior to that of the reference levcromakalim (LCRK). The selective KATP blocker glibenclamide antagonized the above vascular effects, confirming that KATP channels are closely involved in the mechanism of action. The experimental results confirmed the 1,4-benzothiazine nucleus as an optimal scaffold for activators of vascular KATP channels; moreover, the high level of potency exhibited by the 6-acetyl substituted benzothiazine 8, along with the lack of any significant interference with insulin secretion from pancreatic β-cells, paves the way to further develop a new series of potent activators of vascular KATP channels.

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Section: Resultssupporting

confidence: 93%

1,4-Benzothiazine ATP-Sensitive Potassium Channel Openers: Modifications at the C-2 and C-6 Positions

et al. 2013

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“…Most often this distance requirement is met by a three-bond connection at C4 as shown in Figure 2. 27 In this model, Z is the hydrogen-bond accepting group and X and Y are typically part of a ring system such that Z and the benzopyran are held cisoid. Furthermore, the plane of the X-Y-Z system prefers an orthogonal relationship with the plane of the benzopyran for steric reasons and this orthogonal relationship appears to be necessary for good activity.28 Z can be either an electron-rich oxygen atom (as in compounds 1-4 and many of their analogues) or a nitrogen atom.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers

Gadwood¹,

Kamdar²,

Dubray³

et al. 1993

J. Med. Chem.

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A series of novel spirocyclic benzopyran imidazolones were synthesized as rigid analogues of cromakalim. These compounds cause a dose-dependent membrane hyperpolarization of A10 rat aorta cells. This hyperpolarization was blocked by pretreatment with glyburide, indicating that the spirocyclic benzopyran imidazolones were acting by increasing the open probability of ATP-sensitive potassium channels in A10 cells. Representative compounds also showed potent in vivo activity as hypotensive agents in normotensive rats. Many of the compounds described are much more potent than cromakalim both in vitro and in vivo, with one of the most potent compounds being 2,3-dihydro-2,2-dimethyl-6-nitro-2'-(propylamino)spiro[4H-1-benzopyran- 4,4'-[4H]imidazol]-5'(1'H)-one (5r). It is concluded that the N1' nitrogen of the imidazolone is an effective substitute for the carbonyl oxygen of cromakalim. The rigid spirocyclic ring fusion holds this nitrogen in an optimum orientation relative to the benzopyran ring.

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“…For example, the activity of compound (14) without cyclic substitution equals that of compound (1). Attwood et al [55] presumed that the third bond of the substituting group connecting to the benzopyran ring in the 4-position is rich in electrons and has higher density and stronger activity; this seems to support the structural analysis of existing highly active compounds. In addition, the hydroxyl in the 3-position is not always essential for activity, because carbonyl or ester in the 3-position, double bond in the 3-and 4-positions, or hydroxyl in the 3-position substituted with ether or ester also maintain bioactivity [56].…”

Section: Benzopyransmentioning

confidence: 93%

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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The design of a novel class of potassium channel activating drugs, 2-(2,2-dimethylbenzopyran-4-yl)-pyridine-1-oxides

Cited by 21 publications

References 8 publications

1,4-Benzothiazine ATP-Sensitive Potassium Channel Openers: Modifications at the C-2 and C-6 Positions

1,4-Benzothiazine ATP-Sensitive Potassium Channel Openers: Modifications at the C-2 and C-6 Positions

Synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers

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

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