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Chemical Compound Review

SureCN6212361     5-methyl-6-[4-(4-oxopyridin- 1-yl)phenyl]-4...

Synonyms: SKF-95654, AC1L2XUY, SB-95654, LS-172180, Skf 95654, ...
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Disease relevance of Skf 95654


High impact information on Skf 95654

  • 3. Anion-exchange chromatography of the total protein extracted from macrophages resolved two major peaks of cyclic AMP PDE activity that were insensitive to cyclic GMP (10 microM), calmodulin (50 units plus 2 mM CaCl2) and a PDE3 inhibitor, SK&F 95654 (10 microM), but were markedly suppressed by RS-rolipram (10 microM) [2].
  • In contrast, SK&F 95654 failed to suppress proliferation and cytokine generation, and did not elevate the cyclic AMP content in T-cells [3].
  • The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE [4].
  • 4. SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (IC50 = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding [4].
  • 2. In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate [4].

Biological context of Skf 95654

  • The R-enantiomer of SK&F 95654 (IC50 = 0.35 microM) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 microM) [4].

Anatomical context of Skf 95654

  • Myocardial lesions and vascular lesions of the mesentery, spleen, and pancreas were seen 24 hours after dosing with either 50,100, or 200 mg/kg SK&F 95654 [1].

Gene context of Skf 95654

  • Increased expression of CD63 on MC (tissue biomarker of MC), of nitrotyrosine on MC and EC (an indirect indicator of NO in vivo), and of iNOS on MC and EC (source of NO) suggest that NO produced by activated and degranulated MC as well as activated EC play an important role in SK&F 95654-induced mesenteric vascular injury [5].

Analytical, diagnostic and therapeutic context of Skf 95654

  • 3. Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dp/dtmax in the range 10-50 micrograms kg-1 [4].
  • Groups of 3 male beagle dogs received a single 2-hr infusion of SK&F 95654 at 8 mg/kg/hr and the characteristics of the coronary arterial lesions were evaluated at 1, 3, 10, and 34 days postdosing by light, scanning, and transmission electron microscopy [6].
  • Sprague-Dawley rats received either a single sc injection of 50, 100, or 200 mg/kg SK&F 95654 and were euthanized at 24 hours after administration of the drug (Study 1), or were given a single subcutaneous (sc) injection of 100 mg/kg SK&F 95654 and euthanized at 1, 2, 4, 6, 8,12, 24 hours, or 2 weeks after treatment (Study 2) [1].


  1. SK&F 95654-induced acute cardiovascular toxicity in Sprague-Dawley rats--histopathologic, electron microscopic, and immunohistochemical studies. Zhang, J., Herman, E.H., Knapton, A., Chadwick, D.P., Whitehurst, V.E., Koerner, J.E., Papoian, T., Ferrans, V.J., Sistare, F.D. Toxicologic pathology. (2002) [Pubmed]
  2. Characterization of phosphodiesterase 4 in guinea-pig macrophages: multiple activities, association states and sensitivity to selective inhibitors. Kelly, J.J., Barnes, P.J., Giembycz, M.A. Br. J. Pharmacol. (1998) [Pubmed]
  3. Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Giembycz, M.A., Corrigan, C.J., Seybold, J., Newton, R., Barnes, P.J. Br. J. Pharmacol. (1996) [Pubmed]
  4. The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function. Murray, K.J., Eden, R.J., Dolan, J.S., Grimsditch, D.C., Stutchbury, C.A., Patel, B., Knowles, A., Worby, A., Lynham, J.A., Coates, W.J. Br. J. Pharmacol. (1992) [Pubmed]
  5. Mechanisms and biomarkers of cardiovascular injury induced by phosphodiesterase inhibitor III SK&F 95654 in the spontaneously hypertensive rat. Zhang, J., Herman, E.H., Robertson, D.G., Reily, M.D., Knapton, A., Ratajczak, H.V., Rifai, N., Honchel, R., Blanchard, K.T., Stoll, R.E., Sistare, F.D. Toxicologic pathology. (2006) [Pubmed]
  6. Characterization of coronary arterial lesions in the dog following administration of SK&F 95654, a phosphodiesterase III inhibitor. Joseph, E.C., Jones, H.B., Kerns, W.D. Toxicologic pathology. (1996) [Pubmed]
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