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Vasopressor Properties of Nitric Oxide Synthase Inhibitor T1059. Part I: Synthesis, Toxicity, NOS-Inhibition Activity, and Hemodynamic Effects Under Normotensive Conditions

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Pharmaceutical Chemistry Journal Aims and scope

Compound T1059 (1-cyclohexanecarbonyl-2-ethylisothiourea hydrobromide) was found to be water soluble, moderately toxic (i.p. LD16 and LD50 of 274 and 380 mg/kg), and capable of competitively inhibiting nitric-oxide synthase (NOS) activity with significant selectivity toward inducible and endothelial isoforms (IC50 for nNOS, iNOS, and eNOS of 60.3, 1.8, and 3.2 μM, respectively). T1059 was rapidly absorbed after a single i.p. injection (dose range 10 – 30 mg/kg) and distributed in tissues, causing pronounced suppression of endogenous NO production. T1059 at a dose of 10 mg/kg in normotensive anesthetized Wistar rats produced long-term vasoconstriction. The observed changes in vascular tone did not influence inotropic heart function but were accompanied by weak bradycardia.

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Acknowledgments

The work was sponsored in part by an RFBR grant and the Government of Kaluga Oblast (12-04-97524-p-tsentr-a).

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Authors and Affiliations

  1. A. F. Tsyb Medical Radiological Research Center, Branch of National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 4 Koroleva St., Obninsk, Kaluga Oblast, 249036, Russia

    M. V. Filimonova, L. I. Shevchenko, V. M. Makarchuk, E. A. Chesnakova, V. I. Surinova, A. S. Shevchuk & A. S. Filimonov

  2. Zakusov Institute of Pharmacology, Russian Academy of Medical Sciences, 8 Baltiiskaya St., Moscow, 125315, Russia

    S. A. Kryzhanovskii

  3. N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 Kosygina St., Moscow, 119334, Russia

    T. F. Shevchenko, A. E. Bugrova & G. R. Kalamkarov

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  1. M. V. Filimonova
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  2. L. I. Shevchenko
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  3. V. M. Makarchuk
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  4. E. A. Chesnakova
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  5. V. I. Surinova
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  6. A. S. Shevchuk
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  7. A. S. Filimonov
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  8. S. A. Kryzhanovskii
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  9. T. F. Shevchenko
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  10. A. E. Bugrova
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  11. G. R. Kalamkarov
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Additional information

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 52, No. 4, pp. 7 – 12, April, 2018.

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Filimonova, M.V., Shevchenko, L.I., Makarchuk, V.M. et al. Vasopressor Properties of Nitric Oxide Synthase Inhibitor T1059. Part I: Synthesis, Toxicity, NOS-Inhibition Activity, and Hemodynamic Effects Under Normotensive Conditions. Pharm Chem J 52, 294–298 (2018). https://doi.org/10.1007/s11094-018-1809-2

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  • DOI: https://doi.org/10.1007/s11094-018-1809-2

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