CHF 2206, a new potent vasodilating and antiaggregating drug as potential nitric oxide donor

Civelli, Maurizio; Caruso, Paola; Giossi, Massimo; Bergamaschi, M. A. C. M.; Razzetti, Roberta; Bongrani, S; Gasco, Alberto

doi:10.1016/0014-2999(94)90077-9

Cited by 14 publications

(18 citation statements)

References 20 publications

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“…These results are consistent with reports that buffer containing reduced thiols such as L-cysteine or glutathione, which serve as a source of thiols equivalent to the mercarpto groups present in plasma, are required for the release of NO from a furoxan moiety [Civelli et al, 1994[Civelli et al, , 1996Medana et al, 1999]. In this regard, it is interesting that the C-4 2-trifluoromethylphenyl (22-24) and 4-benzofurazanyl 42-44) compounds that release NO more effectively in the absence of Lcysteine (7.0-11.0% range), relative to the related C-4 pyridyl compounds (45-53) that release a negligible amount of NO (0.8-1.2% range), do not induce an agonist contractile effect (22)(23)(24)42) or induce a modest increase in GPILSM contractility (43)(44) in the absence of carbachol.…”

Section: Nitric Oxide Release and Qsarssupporting

confidence: 94%

Syntheses, calcium channel agonist‐antagonist modulation effects, and nitric oxide release studies of [3‐(Benzenesulfonyl)furoxan‐4‐yloxy]alkyl 1,4‐Dihydro‐2,6‐dimethyl‐5‐nitro‐4‐(2‐trifluoromethylphenyl, benzofurazan‐4‐yl, 2‐, 3‐, or 4‐pyridyl)‐3‐pyridinecarboxylates

Nguyen

McEwen

et al. 2002

Drug Development Research

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A group of racemic 1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylates possessing either a C-4 2-trifluoromethylphenyl (22-24), benzofurazan-4-yl (42-44), 2-pyridyl (45-47), 3-pyridyl (48-50), or 4-pyridyl (51-53), substituent in conjunction with a nitric oxide donor C-3 ester [3-(benzenesulfonyl)furoxan-4-yloxy]alkyl substituent were synthesized using modified Hantzsch reactions. Compounds 45-53 having a C-4 2-, 3-, or 4-pyridyl substituent exhibited more potent in vitro calcium channel antagonist activity (IC 50 's in the 0.46 to 5.23 mM range) on guinea pig ileum longitudinal smooth muscle (GPILSM) than related analogs having a C-4 2-trilfuoromethylphenyl (22-24) or benzofurazan-4-yl (42, 44) substituent (IC 50 Z 29.91 mM). The point of attachment of the pyridyl ring (2-, 3-, or 4-), and the length of the C-3 ester alkyl spacer [-CH 2 (CH 2 )n, n ¼ 1-3], were not determinants of smooth muscle calcium channel antagonist activity. Replacement of the C-3 ester methyl substituent of Bay K 8644, or the ester isopropyl substituent of the 4-(pyridyl) isomers 4a-c by a [3-(benzensulfonyl)furoxan-4-yloxy]alkyl moiety retained the desired calcium channel agonist (positive inotropic) effect on guinea pig left atrium (GPLA). Compounds having C-4 3-pyridyl (48-50), or 4-pyridyl (51-53), substituents were the most potent cardiac positive inotropes (EC 50 's in the 3.02 to 19.74 mM range) relative to the reference drug Bay K 8644 IC 50 ¼ 0.77 mM). The % nitric oxide released in vitro in the presence of L-cysteine for this group of compounds was higher (36-74% range) than for the reference drug glycerol trinitrate (20%). A quantitative structure-activity analysis showed an inverse correlation between a molecular weight (MW) descriptor and % nitric oxide released. Model hybrid (calcium channel modulation, nitric oxide donor) compounds that show dual cardioselective agonist (positive inotropic)/smooth muscle selective antagonist activities constitute a novel type of 1,4-dihydropyridine calcium channel modulator that provides a potential drug design concept targeted toward the treatment of congestive heart failure, and is a useful probe to study the structure-function relationship of calcium channels. Drug. Dev. Res. 56:1-16, 2002.

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Section: Nitric Oxide Release and Qsarssupporting

confidence: 94%

Syntheses, calcium channel agonist‐antagonist modulation effects, and nitric oxide release studies of [3‐(Benzenesulfonyl)furoxan‐4‐yloxy]alkyl 1,4‐Dihydro‐2,6‐dimethyl‐5‐nitro‐4‐(2‐trifluoromethylphenyl, benzofurazan‐4‐yl, 2‐, 3‐, or 4‐pyridyl)‐3‐pyridinecarboxylates

Nguyen

McEwen

et al. 2002

Drug Development Research

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“…We demonstrated that 1,1-dinitro-ethyl and 4-R-3-(Rsulphonyl)furoxans possess features characteristic of NO, i.e. they induce vasodilatation and inhibition of platelet aggregation (Ghigo et al, 1992;Gasco et al, 1993;Civelli et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363

Civelli¹,

Giossi²,

Caruso³

et al. 1996

British J Pharmacology

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The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4‐ethoxy‐3‐phenylsulphonylfuroxan), were investigated. Pre‐incubation of CHF 2363 with human platelet‐rich plasma produced a concentration‐dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3‐Isobutyl‐1‐methyl‐xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363. CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN). Increasing concentrations of CHF 2363 elevated platelet guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels. Adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels were unaffected. Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration‐dependently released nitric oxide (NO) in platelet‐rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels. After exposure of rat aortic strips to supramaximal concentrations of GTN (550 μm), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold. It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.

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“…Elemental analyses (C, H, N) were performed by REDOX (Monza). Compounds 1a [14], 2a [15], 1b [9], and 2b [16] were synthesized as described elsewhere.…”

Section: Resultsmentioning

confidence: 99%

“…This indicates that the vasodilator activity of these specific products is not NO dependent but probably connected with their tissue toxicity. C NMR spectra were recorded on a Bruker Avance 300 at 300 and 75 MHz, respectively, using SiMe 4 as Table 1 Physicochemical parameters and pharmacological activities of furoxan and furazan sulfonic acids (7,8) and related sulfonamides (9)(10)(11)(12)(13)(14)(15)(16) a Potentiometric titrations were performed in water containing methanol as a cosolvent in different ratios depending on the solubility of compounds: pK a values were determined by extrapolation at 0% methanol using the Yasuda-Shedlovsky procedure (experimental). b NMR determination.…”

Section: Resultsmentioning

confidence: 99%

Unsymmetrically substituted furoxans. Part 19. Methyl and phenylfuroxansulfonic acids and related sulfonamides

Chegaev

Rolando

Guglielmo

et al. 2009

Journal of Heterocyclic Chem

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magnified imageSynthesis, structural characterization, and acid dissociation constants (pKa) of a series of methyl‐ and phenyl‐substituted furoxansulfonic acids and related sulfonamide derivatives, as well as their furazan analogues are described. The ability of furoxans to dilate rat aorta strips precontracted with phenylephrine is reported as an example of their NO‐dependent pharmacological properties. J. Heterocyclic Chem., (2009).

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CHF 2206, a new potent vasodilating and antiaggregating drug as potential nitric oxide donor

Cited by 14 publications

References 20 publications

The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363

Unsymmetrically substituted furoxans. Part 19. Methyl and phenylfuroxansulfonic acids and related sulfonamides

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