Synthesis, properties, and pharmacokinetic studies of N2-phenylguanine derivatives as inhibitors of herpes simplex virus thymidine kinases.
Two series of selective inhibitors of herpes simplex virus types 1 and 2 (HSV1,2) thymidine kinases (TK) have been developed as potential treatment of recurrent virus infections. Among compounds related to the potent base analog N2-[m-(trifluoromethyl)phenyl]guanine (mCF3-PG), none was a more potent inhibitor than mCF3PG itself. Compounds related to the nucleoside N2-phenyl-2'-deoxyguanosine (PhdG), but with alkyl, hydroxyalkyl, and related substituents at the 9-position in place of the glycosyl group of PhdG, retained significant but variable inhibitory potencies against the HSV TKs. The most potent inhibitor of HSV1 TK among 9-substituted derivatives, 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG), was a competitive inhibitor with respect to the substrate thymidine but was not itself a substrate for the enzyme. Water solubilities and 1-octanol:water partition coefficients for the 9-substituted N2-phenylguanines were linearly but oppositely related to the sum of hydrophobic fragmental constants (sigma f) of the 9-substituents. Four of the inhibitors were given as solutions to mice by iv and ip routes, and the time course of their plasma concentrations was determined by HPLC analysis of the parent compounds. HBPG was completely absorbed by the ip route, and the plasma concentration could be prolonged by use of suspension formulations. HBPG is a candidate for animal trials of the ability of TK inhibitors to prevent recurrent herpes virus infections.
Xu
H
H
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
Maga
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Focher
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Smith
E R
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Spadari
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Gambino
J
J
Wright
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GE
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D018258:Herpesvirus 2, Human / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D012995:Solubility; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D014867:Water / Q000737:chemistry
C091724:9-(4-hydroxybutyl)-N(2)-phenylguanine; D000998:Antiviral Agents; D008055:Lipids; D014867:Water; C088966:N(2)-phenylguanine; D006147:Guanine; D013937:Thymidine Kinase