Delving into the Latest Updates on BRL-55834 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

BRL 55834

Target

Potassium channel

Mechanism

Potassium channel agonists

Therapeutic Areas

Immune System DiseasesRespiratory Diseases

Active Indication-

Inactive Indication

AsthmaPulmonary Disease, Chronic Obstructive

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

GSK Plc

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC18H20F5NO3

InChIKeyZSUFQZNGDIXQAD-CABCVRRESA-N

CAS Registry131899-25-7

Stimulation of vascular endothelial muscarinic receptors by acetylcholine (ACh) leads to the formation of an endothelium-derived relaxing factor (EDRF), which is generally accepted to be nitric oxide (NO). Recent evidence, however, suggests that NO may be only one of several EDRFs mediating the vasodilator response to ACh. Since this NO-independent vasodilator response to ACh has been hypothesized to be dependent upon K(+) channel activation, the current study was undertaken to investigate the role of K(+) channels in mediating the hindlimb vasodilator responses to ACh in vivo. Additionally, since variations in vascular tone can complicate the analysis of responses, the level of vascular tone was maintained at a similar level throughout the study so that responses could be compared directly. The results of the present study demonstrate that the vasodilator response to ACh possesses a significant component that is independent of NO production. The K(Ca) channel blockers charybdotoxin and apamin, but not K(+)-ATP channel blocker U37883A or the COX antagonist meclofenamate, attenuated the NO-independent component of the vasodilator response to ACh. This suggests that K(Ca) channels, but not K(+)-ATP channels or COX products, are involved in mediating the L-NAME resistant response to ACh. Further, the inhibition of the ACh vasodilator response by the K(+)-ATP opener BRL55834 suggests that the response is dependent upon membrane hyperpolarization. These data suggest that the mechanism mediating ACh responses in the hindlimb vascular bed of the rat are complex and may involve several signaling pathways.

01 Nov 1999·Chinese medical journalQ3 · MEDICINE

Effects of BRL 55 834 on allergen-induced bronchoconstriction and airway inflammation in sensitized guinea pigs.

Q3 · MEDICINE

ArticleOA

Author: Z Yan ; Y Ye ; W Luo ; Q Xiu ; Q Zhu ; Z Shi

OBJECTIVE:

To investigate the effects of potassium channel activator on allergen-induced bronchoconstriction and airway inflammation and to discuss which role it plays in asthma therapy.

METHODS:

Airway insufflation pressure, examination of inflammatory cells in bronchial alveolar lavage fluid, analysis of airway pathology and airway Evans blue dye extravasation measurement were employed to detect airway resistance and airway inflammatory responses.

RESULTS:

[(3s, 4R)-3, 4-dihydro-2, 2-dimethyl-4-(2-oxopiperidin-l-yl)-6-pentafluoroethyl-2H-1-benzopyran-3-ol] (BRL) 55 834 (8 micrograms/kg) inhibited not only ovalbumin-induced airway insufflation pressure increase but also inflammatory cell infiltration (ICI) in sensitized guinea-pigs; moreover, it did not decrease blood pressure; in contrast to BRL 55 834, single dose of BRL 38 227 (200 micrograms/kg) and verapamil (0.5 mg/kg) had a little effect on ICI; single dose of aminophylline (25 mg/kg) and dexamethasone (1 mg/kg) could not inhibit ICI, but the former could inhibit airway insufflation increase; drugs, besides aminophylline, could reduce microvascular leakage; single dose of BRL 38 227, verapamil and dexamethasone had no inhibition of airway insufflation pressure; BRL 38 227 and verapamil decreased blood pressure markedly.

CONCLUSIONS:

Selective potassium channel activator BRL 55 834 not only decreases airway resistance, but also inhibit airway inflammation, and both of them are of benefit to asthma therapy.

01 Apr 1998·Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases

[Antigen-induced airway leakage in asthmatic guinea-pigs and the effects of BRL 55834].

Article

Author: Yan, Z ; Shi, Z ; Luo, W

OBJECTIVE:

To understand the role of airway leakage in asthma attack and investigate the effects of BRL 55834 on prophylaxis and treatment of asthma.

METHOD:

Ten normal and seventeen sensitized guinea-pigs were divided into 5 groups. After being anesthetized, right carotid artery, right jugular vein and trachea were cannulated to monitor systemic blood pressure, inject drugs, mechanical ventilate and record airway insufflation pressure (AIP). All animals were pretreated with atropine and propranolol (1 mg/kg) 30 min before experiment. DMSO or BRL 55834 was administered intravenously 2 min before intravenous injection of evans blue (EB, 30 mg/kg), Ovalbumin (OA, 3 mg/ml) was inhaled using an ultrasonic nebulier for 30 seconds 1 min after injection of EB.

RESULT:

(1) BRL 55834 (8 micrograms/kg) did not inhibit airway leakage in normal guinea-pig; (2) Airway leakage increased in sensitized guinea-pigs significantly after inhaling OA, 87 +/- 19 ng dye/mg tissue vs 53 +/- 7 ng dye/mg tissue in trachea (Tr); 119 +/- 67 ng dye/mg tissue vs 79 +/- 46 ng dye/mg tissue in main bronchus (MB); 65 +/- 44 ng dye/mg tissue vs 46 +/- 17 ng dye/mg tissue in central pulmonary airway (CiPA) and 50 +/- 31 ng dye/mg tissue vs 32 +/- 4 ng dye/mg tissue in peripheral pulmonary airway (PiPA, P < 0.05). (3) BRL 55834 inhibited airway leakage contrast to DMSO, especially in CiPA and PiPA, with an inhibition of 48% (Tr, P < 0.05), 57% (MB, P < 0.01), 44% (CiPA, P < 0.05), and 46% (PiPA, P < 0.05) after injection of BRL 55834 8 micrograms/kg, and 46% (Tr, P < 0.05), 57% (MB, P < 0.01), 56%(CiPA, P < 0.01) and 55% (PiPA, P < 0.01) after injection of BRL 55834 16 micrograms/kg, respectively. (4) BRL 55834 decreased base AIP in all groups, and inhibited OA-induced AIP increasing in sensitized guinea-pigs, with an inhibition of 49% (BRL 55834 8 micrograms/kg) and 57% (BRL 55834 16 micrograms/kg) in contrast to DMSO. BRL 55834 had a little side-effect on cardiovascular system, but without statistical significance.

CONCLUSION:

Airway leakage is one of the most important components in asthma attack, BRL 55834, a selective potassium channel activator, not only decreases airway leakage, but also inhibits OA-induced increase in airway resistance. All these are beneficial to prophylaxis and treatment of asthma.

100 Deals associated with BRL-55834

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