SYNTHESIS, PROPERTIES, AND PHARMACOKINETIC STUDIES OF N-2-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 tr eatment of recurrent virus infections. Among compounds related to the potent base analog N-2-[m-(trifluoromethyl)phenyl]guanine (mCF(3)PG), none was a more potent inhibitor than mCF(3)PG itself. Compounds relat ed to the nucleoside N-2-phenyl-2'-deoxyguanosine (PhdG), but with alk yl, hydroxyalkyl, and related substituents at the 9-position in place of the glycosyl group of PhdG, retained significant but variable inhib itory potencies against the HSV TKs. The most potent inhibitor of HSV1 TK among 9-substituted derivatives, 9-(4-hydroxybutyl)-N-2-phenylguan ine (HBPG), was a competitive inhibitor with respect to the substrate thymidine but was not itself a substrate for the enzyme. Water solubil ities and 1-octanol:water partition coefficients for the 9-substituted N-2-phenylguanines were linearly but oppositely related to the sum of hydrophobic fragmental constants (Sigma f) of the 9-substituents. Fou r of the inhibitors were given as solutions to mice by iv and ip route s, and the time course of their plasma concentrations was determined b y HPLC analysis of the parent compounds. HBPG was completely absorbed by the ip route, and the plasma concentration could be prolonged by us e of suspension formulations. HBPG is a candidate for animal trials of the ability of TK inhibitors to prevent recurrent herpes virus infect ions.