Pharmacology of ZM244085: A Novel Bladder‐Selective Dihydropyridine K<sub>ATP</sub> Channel Activator

Li, Jack H.

doi:10.1111/j.1527-3466.1997.tb00332.x

Cited by 11 publications

(4 citation statements)

References 21 publications

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“…ZM-244085 62 (scheme 10) is an example for DHP-like KCOs [83,84]. Effects on low and high KCl induced contractions, 86 Rb efflux, and [ 3 H]P1075 binding in guineapig bladder strips were used to characterize its in vitro KCO properties [83].…”

Section: Dhp-related Structuresmentioning

confidence: 99%

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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: Dhp-related Structuresmentioning

confidence: 99%

“…Effects on low and high KCl induced contractions, 86 Rb efflux, and [ 3 H]P1075 binding in guineapig bladder strips were used to characterize its in vitro KCO properties [83]. ZM-244085 possesses in vivo bladder selectivity [84].…”

Section: Dhp-related Structuresmentioning

confidence: 99%

Structure-Activity Relationships of KATP Channel Openers

Mannhold¹

2006

CTMC

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“…8,9 In vivo activity has also been showed with a number of K ATP openers. [9][10][11][12][13][14] However, the clinical data for KCOs is restricted to a small pilot clinical study with cromakalim on patients with detrusor instability or detrusor hyperreflexia. In this study the nonselective KCO, cromakalim, demonstrated an improvement in the symptoms of bladder overactivity.…”

Section: Introductionmentioning

confidence: 99%

“…Several K ATP openers such as cromakalim and pinacidil have been shown to relax in vitro bladder smooth muscle from humans, pigs, rats, or guinea pigs. , In vivo activity has also been showed with a number of K ATP openers. − However, the clinical data for KCOs is restricted to a small pilot clinical study with cromakalim on patients with detrusor instability or detrusor hyperreflexia. In this study the nonselective KCO, cromakalim, demonstrated an improvement in the symptoms of bladder overactivity .…”

Section: Introductionmentioning

confidence: 99%

Structure−Activity Studies of Novel Cyanoguanidine ATP-Sensitive Potassium Channel Openers for the Treatment of Overactive Bladder

et al. 2007

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A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.

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K_ATP channel openers: Structure‐activity relationships and therapeutic potential

Mannhold

2003

Medicinal Research Reviews

157

111

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ATP-sensitive potassium channels (K(ATP) channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. K(ATP) channels were identified in a variety of tissues including muscle cells, pancreatic beta-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, K(ATP) channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via K(ATP) channels. 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), for example, 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.

show abstract

Pharmacology of ZM244085: A Novel Bladder‐Selective Dihydropyridine K_ATP Channel Activator

Cited by 11 publications

References 21 publications

Structure-Activity Relationships of KATP Channel Openers

Structure-Activity Relationships of KATP Channel Openers

Structure−Activity Studies of Novel Cyanoguanidine ATP-Sensitive Potassium Channel Openers for the Treatment of Overactive Bladder

K_ATP channel openers: Structure‐activity relationships and therapeutic potential

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Pharmacology of ZM244085: A Novel Bladder‐Selective Dihydropyridine KATP Channel Activator

Cited by 11 publications

References 21 publications

Structure-Activity Relationships of KATP Channel Openers

Structure-Activity Relationships of KATP Channel Openers

Structure−Activity Studies of Novel Cyanoguanidine ATP-Sensitive Potassium Channel Openers for the Treatment of Overactive Bladder

KATP channel openers: Structure‐activity relationships and therapeutic potential

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Product

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Pharmacology of ZM244085: A Novel Bladder‐Selective Dihydropyridine K_ATP Channel Activator

K_ATP channel openers: Structure‐activity relationships and therapeutic potential