COMPARATIVE INVITRO AND INVIVO ACTIVITIES OF 2 9-DEAZAGUANINE ANALOG INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE, CI-972 AND PD-141955

An in-parallel comparison is presented of the in vitro and in vivo properties of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase (PNP), CI-972 [8-amino-9-deaza-9-(3-thienylmethyl)guanine] and PD 141955 [9-deaza-9-(3-thienylmethyl)guanine] (published K(i) values of 0.83-8.0 and 0.08-mu-M, respectively). Despite structural similarities, PD 141955 was considerably more potent and active in all systems studied. The respective IC50 values for inhibition of MOLT-4 cell growth in the absence and presence of 10-mu-M 2'-deoxyguanosine (GdR) were > 50 and 5.06-mu-M for CI-972 and 15.4 and 0.061-mu-M for PD 141955. PD 141955 induced accumulation of dGTP in GdR-treated MOLT-4 and CEM cells at log-lower concentrations than were required of CI-972, and the magnitude of dGTP accumulation in PD 141955-treated T cell cultures was markedly greater (e.g. 366 vs 100-mu-mol/10(6) CEM cells at 10-mu-M). PD 141955 administered orally produced a dose-dependent elevation of plasma inosine and guanosine in rats over a broad concentration range. Mean plasma inosine concentrations following a 150 mg/kg p.o. dose peaked at 6.21 and 13.2-mu-M in CI-972 and PD 141955-treated rats, respectively. Low levels of inosine were detectable at 50-mu-g/kg following oral administration of PD 141955.