Arylcyanoguanidines as Activators of Kir6.2/SUR1K<sub>ATP</sub> Channels and Inhibitors of Insulin Release

Tagmose, Tina M.; Schou, Søren Christian; Mogensen, John P.; Nielsen, Flemming; Arkhammar, Per; Wahl, Philip; Hansen, Birgit Sehested; Worsaae, Anne; Boonen, Harrie C. M.; Antoine, Marie-Hélène; Lebrun, Philippe; Hansen, John Bondo

doi:10.1021/jm031018y

Cited by 12 publications

(6 citation statements)

References 34 publications

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“…Tagmose et al [77] found that the replacement of the pyridine ring in pinacidil with a 3,5-disubstituted phenyl group yielded compounds which activate β-cell K ATP channels at concentrations which do not relax smooth muscle. β-Cell activity of the compounds was shown to depend on size and bulkiness of the N-alkyl side chain.…”

Section: Prototypementioning

confidence: 99%

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: Prototypementioning

confidence: 99%

Structure-Activity Relationships of KATP Channel Openers

Mannhold¹

2006

CTMC

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“…Arylcyanoguanidines with short aliphatic side chains (e.g. N -aryl- N' -cyano- N'' -alkyl-guanidines) are known as activators of ATP-sensitive potassium channels and inhibitors of insulin release from beta cells, but small structural changes can dramatically change the efficacy [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug

2009

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BackgroundN-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N''-4-pyridyl guanidine) (CHS 828) is the first candidate drug from a novel group of anti-tumour agents – the pyridyl cyanoguanidines, shown to be potent compounds interfering with cellular metabolism (inhibition of nicotinamide phosphoribosyl transferase) and NF-κB signalling. Substituted cyanoguanidines are also found in anti-hypertensive agents such as the potassium channel opener pinacidil (N-cyano-N'-(4-pyridyl)-N''-(1,2,2-trimethylpropyl)guanidine) and histamine-II receptor antagonists (e.g. cimetidine, N-cyano-N'-methyl-N''-[2-[[(5-methylimidazol-4-yl]methyl]thio]ethyl)guanidine). In animal studies, CHS 828 has shown very promising activity, and phase I and II studies resulted in further development of a with a water soluble prodrug.FindingsTo study the structural requirements for cyanoguanidine cytotoxicity a set of 19 analogues were synthesized. The cytotoxic effects were then studied in ten cell lines selected for different origins and mechanisms of resistance, using the fluorometric microculture cytotoxicity assay (FMCA). The compounds showed varying cytotoxic activity even though the dose-response curves for some analogues were very shallow. Pinacidil and cimetidine were found to be non-toxic in all ten cell lines. Starting with cyanoguanidine as the crucial core it was shown that 4-pyridyl substitution was more efficient than was 3-pyridyl substitution. The 4-pyridyl cyanoguanidine moiety should be linked by an alkyl chain, optimally a hexyl, heptyl or octyl chain, to a bulky end group. The exact composition of this end group did not seem to be of crucial importance; when the end group was a mono-substituted phenyl ring it was shown that the preferred position was 4-substitution, followed by 3- and, finally, 2-substitution as the least active. Whether the substituent was a chloro, nitro or methoxy substituent seemed to be of minor importance. Finally, the activity patterns in the ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients.ConclusionAccording to this structure-activity relationship (SAR) study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.

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“…Piperidinone derivatives act as potential inhibitors of human placental aromatase in vitro (Baroudi et al, 1996). In particular, N-cyano compounds have been found as activators of ATP-sensitive potassium channels and inhibitors of insulin release (Manley et al, 1993;Tagmose et al, 2004;Yoshiizumi et al, 1997). This has prompted us to carry out accurate determinations of the crystal structures of a host of N-cyano-substituted piperidinone derivatives.…”

Section: Commentmentioning

confidence: 99%