<i>In vitro</i> investigation of the bladder‐vascular selectivity of levcromakalim and YM934 in human tissues

Chess-Williams, Russ; Sw, Martin; Korstanje, Cees; Chapple, Christopher R.

doi:10.1046/j.1464-410x.1999.00101.x

Cited by 16 publications

(6 citation statements)

References 22 publications

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“…Our studies show that YM934 was more potent than (-)-cromakalim on both a dose (4.1-fold) and plasma concentration (2.9-fold) basis. These data are in agreement with previous reports suggesting a 2.7-fold potency di¡erence in rat portal vein [Uchida et al, 1994] and a 2-fold di¡erence in human detrusor strips [Martin et al, 1997;Chess-Williams et al, 1999]. Foster et al [1989] previously reported that cromakalim at 0.3 mg/kg, i.v.…”

Section: Discussionsupporting

confidence: 93%

Effects of ATP‐sensitive K⁺ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

Fey

Gopalakrishnan

Strake

et al. 2003

Neurourology and Urodynamics

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The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.

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Section: Discussionsupporting

confidence: 93%

Effects of ATP‐sensitive K⁺ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

Fey

Gopalakrishnan

Strake

et al. 2003

Neurourology and Urodynamics

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“…Agents are therefore needed that offer a greater selectivity for the bladder over the vasculature. YM-934 has been found to exert bladder:vascular selectivity in human tissues in vitro [59] but this is minor and of no clinical significance. ZD-6169 reduces the frequency of micturition in rats without any cardiovascular side effects [53] and inhibits bladder hyperactivity in rats at doses that produce minimal changes in blood pressure and heart rate [54], but only clinical trials will establish whether this selectivity is of therapeutic value.…”

Section: Potassium Channelsmentioning

confidence: 99%

Potential therapeutic targets for the treatment of detrusor overactivity

Chess‐Williams¹

2004

Expert Opinion on Therapeutic Targets

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Current treatments for the overactive detrusor are poorly tolerated and can exert significant adverse effects. Possible targets for the development of new treatments are considered. Potential targets in four locations are examined: detrusor smooth muscle, urothelium, peripheral nerves and the CNS. In the detrusor, the role of various muscarinic receptor subtypes is discussed and beta-adrenoceptor agonists, phosphodiesterase inhibitors and potassium channel openers, all of which inhibit detrusor contractility, are considered for drug development. In the urothelium, a number of substances are released that affect bladder function including ATP, acetylcholine and an inhibitory factor that has yet to be identified. All three systems have the potential to be novel targets for drug development. Other possible therapeutic targets are the mechanisms influencing transmitter release in the bladder, for example, prejunctional 5-hydroxytryptamine (5-HT) 4 receptors. Finally, targets within the CNS and spinal cord are considered, including opioid receptors, 5-HT receptors and alpha-adrenoceptors.

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“…The 12)] which is a potent vasodilator, that is 3-times more potent than LCRK, with particularly pronounced effect on coronary artery [92]. YM-934 (52) has been extensively evaluated in an attempt to delineate its pharmacological profile on cardiovascular [93][94][95], respiratory [96,97], and urinary [98,99] systems. A recent article by Astellas Pharmaceutical confirmed that a non-hypotensive dose of YM-934 significantly decreased coronary peripheral vascular resistances, increased coronary flow and enhanced myocardial recovery from transient coronary flow interruption in a dog model of impaired coronary circulation similar to unstable angina [100].…”

Section: Benzoxazinesmentioning

confidence: 99%

From Cromakalim to Different Structural Classes of KATP Channel Openers

Cecchetti¹,

Tabarrini²,

Sabatini³

2006

CTMC

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ATP-Sensitive potassium channel openers (K(ATP)COs) are a group of compounds with a broad spectrum of potential therapeutic applications, as they constitute efficient tools for dampening cell excitability. Interest in the K(ATP)COs was triggered in the early 1980s by the discovery of the benzopyran-based structure cromakalim (CRK), which is a powerful smooth muscle relaxant. CRK can be considered the archetype of K(ATP)COs and is by far the most mimicked structure. In many structure-activity studies various substitutions have been made at the different positions of the benzopyran ring permitting the optimal activity to be correlated with a specific set of structural characteristics and stereochemical features of the molecule. Thus, many potent benzopyran derivatives have been identified. The benzopyran nucleus itself has also been modified in both the aromatic ring and in the pyran moiety. The intention of this review is to bring together all the different structural classes of K(ATP)COs arising from the replacement of CRK benzopyran-based structure with various ring systems; design, structure-activity relationship, and synthesis will be given.

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In vitro investigation of the bladder‐vascular selectivity of levcromakalim and YM934 in human tissues

Abstract: Only minor bladder-vascular selectivity for levcromakalim and YM934 could be detected in vitro. This suggests that neither drug would be tolerated clinically, although the results suggest that further development of bladder-selective KCO agents appears feasible.

Cited by 16 publications

References 22 publications

Effects of ATP‐sensitive K⁺ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

Effects of ATP‐sensitive K⁺ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

Potential therapeutic targets for the treatment of detrusor overactivity

From Cromakalim to Different Structural Classes of KATP Channel Openers

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In vitro investigation of the bladder‐vascular selectivity of levcromakalim and YM934 in human tissues

Abstract: Only minor bladder-vascular selectivity for levcromakalim and YM934 could be detected in vitro. This suggests that neither drug would be tolerated clinically, although the results suggest that further development of bladder-selective KCO agents appears feasible.

Cited by 16 publications

References 22 publications

Effects of ATP‐sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

Effects of ATP‐sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

Potential therapeutic targets for the treatment of detrusor overactivity

From Cromakalim to Different Structural Classes of KATP Channel Openers

Contact Info

Product

Resources

About

Effects of ATP‐sensitive K⁺ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

Effects of ATP‐sensitive K⁺ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction