N,N-disubstituted benzopyran-4-(N′-cyano)carboxamidines, cromakalim analogs with selective activity for guinea pig trachealis

Koga, Hiroshi; Sato, Haruhiko; Ishizawa, Takenori; Kuromaru, Kiyonori; Nabata, Hiroyuki; Imagawa, Jun-ichi; Yoshida, Shoshin; Sugo, Izumi

doi:10.1016/s0960-894x(00)80297-8

Cited by 19 publications

(5 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and helps in the discovery or new compounds with high activities. Compound (74), which was designed based on the model [113], strengthens the dilatation of smooth muscle more than compounds (1), (2), or (3). Compound (75) is obtained by replacing the nitro group in the 6-position by a cyano group, and its vasodilative activity is 100 times that of prototype compounds (1), (2), and (3).…”

Section: Novel Kcos Aliphatic Secondary Amine Compounds and Iptakalimmentioning

confidence: 99%

“…The quantitative structure-activity relationships of the 6-substitution series of compounds indicates that the vasodilative activity and the electrical properties of the 6-substituted group are linearly correlated and that the relationship between the hydrophobic parameter and steric parameter is parabolic. Compounds of general formula (76) have a very strong vasodilative activity, but introducing a carbonyl group to amine decreases the vasodilative activity and increases the diastolic selectivity of airway smooth muscle [113]. Replacing the hydrogen on the 2-methyl by fluorine increases the hydrophobicity in proportion to the number of fluorines.…”

Section: Novel Kcos Aliphatic Secondary Amine Compounds and Iptakalimmentioning

confidence: 99%

See 1 more Smart Citation

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

Wang¹,

Tang²,

Wang³

et al. 2007

CMC

View full text Add to dashboard Cite

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.

show abstract

Section: Novel Kcos Aliphatic Secondary Amine Compounds and Iptakalimmentioning

confidence: 99%

Section: Novel Kcos Aliphatic Secondary Amine Compounds and Iptakalimmentioning

confidence: 99%

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

Wang¹,

Tang²,

Wang³

et al. 2007

CMC

View full text Add to dashboard Cite

show abstract

“…Airways selectivity in vitro exhibits KC-128 22, a member of a series of benzopyran-4-(N'-cyano)carboxamidines [41,42]. Selectivity -quantified by dilator potency in isolated rat aorta versus inhibition of spontaneous tone of isolated guinea-pig trachea -depended on N-substitution within the carboxamidine moiety.…”

Section: Airways Selective Benzopyrans and Dialkylnaphthalenonesmentioning

confidence: 99%

“…In contrast to classical KCOs, the relaxant activity of KC-128 was noncompetitively blocked by glibenclamide, suggesting that KC-128 might target a binding site different from classical KCOs. In a subsequent study [42] the impact of 6-substituents and modifications of the cyanimino group on selectivity were explored. 6-nitro substitution was found optimal; the cyanimino group is essential, its replacements abolished selectivity.…”

Section: Airways Selective Benzopyrans and Dialkylnaphthalenonesmentioning

confidence: 99%

Structure-Activity Relationships of KATP Channel Openers

Mannhold¹

2006

CTMC

View full text Add to dashboard Cite

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.

show abstract

“…Recently, however, several compounds which open KATP but which do not show vascular selectivity have been described Koga et al, 1993;Pirotte et al, 1993;Ishizawa et al, 1994). One of these, the benzopyran derivative BRL55834, is a bronchodilator at doses which have relatively little effect on blood pressure when administered to animals either intravenously, intraduodenally or by inhalation (Bowring et al, 1993;Arch et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide‐resistant, ATP‐sensitive potassium current

Edwards

Schneider

Niederste-Hollenberg

et al. 1995

British J Pharmacology

View full text Add to dashboard Cite

1 The effects of the benzopyran K-channel opener, BRL55834, on mechanical activity in bovine trachealis and rat portal vein were studied together with membrane currents in freshly-isolated single cells derived from these tissues. 2 BRL55834 (3 nM-1 iM) produced a concentration-dependent relaxation of bovine trachealis precontracted with 100 gM histamine and reduced the spontaneous mechanical activity of rat portal veins, effects which were antagonized by glibenclamide (1 -10 gM) but were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine trachealis.3 BRL55834 (10 nM-10 gM) did not relax segments of bovine trachealis precontracted with 80 mM KCl.4 In some freshly-isolated single cells from bovine trachealis held at -10 mV, BRL55834 (3 giM) induced a time-independent outward K-current which was partially resistant to inhibition by glibenclamide (10 giM). In other cells, a very noisy, outwardly-rectifying and charybdotoxin-sensitive current developed in the presence of BRL55834 (3 giM) and in time-matched control cells. 5 In freshly-isolated single cells from rat portal vein held at -10 mV, BRL55834 (3 gM) induced a timeand calcium-independent outward K-current which was partially resistant (approximately 25% inhibition at + 40 mV) to subsequent inhibition by glibenclamide (10 gM). In contrast, levcromakalim induced a time-independent outward K-current which was completely inhibited by glibenclamide 10 gM. 6 With the non-hydrolysable ATP analogue, AMP-PCP (5 mM), in the pipette, the ability of BRL55834 to induce a time-independent K-current in portal vein cells was markedly reduced (approximately 80% inhibition at + 40 mV) whereas the effects of 10 gM levcromakalim were totally inhibited. 7 The glibenclamide-resistant current component induced by BRL55834 was totally inhibited by phentolamine (100 gM), a concentration that had no effect on the peak current (IBK(Ca)) induced by NS1619 (33 giM).8 Stationary fluctuation analysis of the noise associated with the glibenclamide-insensitive K-current induced by BRL55834 in rat portal vein cells indicated that the unitary current flowing through the underlying channels was 0.26 pA at -10 mV, a value inconsistent with the involvement of BKca.9 It is concluded that the relaxations of both bovine trachea and rat portal vein produced by BRL55834 are associated with the opening of K-channels. These are probably identical to the ATPsensitive K-channel opened by levcromakalim, although the involvement of an additional K-channel cannot be excluded. The reduced sensitivity of the BRL55834-induced changes to glibenclamide and to AMP-PCP may result from avid binding of BRL55834 to its site of action.

show abstract

N,N-disubstituted benzopyran-4-(N′-cyano)carboxamidines, cromakalim analogs with selective activity for guinea pig trachealis

Cited by 19 publications

References 6 publications

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

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

Structure-Activity Relationships of KATP Channel Openers

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide‐resistant, ATP‐sensitive potassium current

Contact Info

Product

Resources

About