文献-Inactivators of herpes simplex virus ribonucleotide reductase hematological profiles and in vivo potentiation of the antiviral a.docxVIP

文献-Inactivators of herpes simplex virus ribonucleotide reductase hematological profiles and in vivo potentiation of the antiviral a.docx

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PAGE \* MERGEFORMAT PAGE \* MERGEFORMAT # SPECTOR ET AL. Antimicrob. Agents Chemother. Vol. Vol. 36, 1992 POTENTIATORS OF ACYCLOVIR PAGE \* MERGEFORMAT # Vol. 36, No. 5 Vol. 36, No. 5 PAGE \* MERGEFORMAT PAGE \* MERGEFORMAT # Antimicrobial Agents and Chemotherapy, May 1992, p. 934-937 0066-4804/92/050934-04$02.00/0 Copyright ? 1992, American Society for Microbiology Inactivators of Herpes Simplex Virus Ribonucleotide Reductase: Hematological Profiles and In Vivo Potentiation of the Antiviral Activity of Acyclovir THOMAS SPECTOR,1* DAVID C. LOBE,2 M. NIXON ELLIS,2 TODD A. BLUMENKOPF,3 and GEORGE M. SZCZECH4 Divisions of Experimental Therapy,1 Virology,2 Organic Chemistry,3 and Toxicology and Pathology,4 Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709 Received 12 November 1991/Accepted 21 January 1992 A1110U (BW 1110U81) is an inactivator of herpesvirus ribonucleotide reductases and a potentiator of the antiviral activity of acyclovir (ACV) (T. Spector, J. A. Harrington, R. W. Morrison, Jr., C. U. Lambe, D. J. Nelson, D. R. Averett, K. Biron, and P. A. Furman, Proc. Natl. Acad. Sci. USA 86:1051-1055,1989) that was subsequently found to cause hematological toxicity at high oral doses in rats. Eleven structurally related inactivators of herpes simplex virus (HSV) ribonucleotide reductase were therefore tested in vivo for hematological toxicity and for potentiation of ACV. None of the novel ribonucleotide reductase inactivators was hematologically toxic to rats following oral dosing at 60 mg/kg/day for 30 days. Four of these inactivators statistically improved the antiviral topical potency of ACV on HSV type 1-infected nude mice. A promising compound,2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone (BW 348U87), was studied more extensively in two in vivo models: dorsum-infected athymic nude mice and snout-iofected hairless mice. BW 348U87 significantly potentiated the antiviral activity of ACV against all virus

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