Selective activity and cellular pharmacology of (1R-1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine in herpesvirus- infected cells

G Yamanaka, AV Tuomari, M Hagen, B McGeever-Rubin, B Terry, M Haffey, GS Bisacchi and AK Field

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.

The cycloburtane nucleoside analog (1R-1 alpha,2 beta,3 alpha)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine [(R)-BHCG or SQ 34,514] was recently synthesized and shown to be the active enantiomer of (+/-)- BHCG (SQ 33,054), a potent inhibitor of several strains of herpesviruses [J. Med. Chem 34:1415-1421 (1991); Antiviral Res. 13:41- 52 (1990)]. In plaque reduction assays, (R)-BHCG was about 1000 times more active than its S-enantiomer on herpes simplex virus type I (HSV- 1) and over 200 times more active against a thymidine kinase-deficient mutant HSV-1 and human cytomegalovirus (HCMV). We now show that both (R)-BHCG and (S)-BHCG are efficiently phosphorylated to their mono-, di- , and triphosphates by HSV-1-infected cells, in a manner similar to that of acyclovir [Proc. Natl. Acad. Sci. USA 74:5716-5720 (1977)]. The uptake of both enantiomers was greatly increased upon infection; however, (S)-BHCG was taken up to about twice the extent of (R)-BHCG and accumulated primarily as the mono- and diphosphates. (R)-BHCG accumulated primarily as the triphosphate, and accumulation was linear with both time and added drug concentration. The triphosphate had an apparent half-life of about 10 hr. Metabolic studies using HCMV- infected cells showed only a small degree of phosphorylation of (R)- BHCG and none of (S)-BHCG. When cells were labeled with 25 microM (R)- BHCG, the amount of (R)-BHCG triphosphate formed was less than 0.5 pmol/10(6) cells. Interestingly, the ED50 value of (R)-BHCG is about 100-fold higher against HCMV than against HSV-1, and the relative levels of (R)-BHCG triphosphate formed in cells infected by the two viruses are roughly proportional to the antiviral activities.

Volume 40, Issue 3, pp. 446-453, 09/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics