PD-141955 AND CI-972 - 9-DEAZAGUANINE ANALOG PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITORS .1. SUPPRESSION OF THE HUMAN MIXED LYMPHOCYTE-REACTION (MLR)

Inhibitors of purine nucleoside phosphorylase (PNP) are of interest as potential T-cell-selective immunosuppressive agents and for other use s. PD 141955 (9-deaza-9-(3-thienylmethyl)guanine; 3-thienylmethyl)-4H- pyrrolo[3,2-d]pyrimidin-4-one) is 12- to 100-fold more potent than CI- 972 (8-amino-9-deaza-9-(3-thienylmethyl)guanine; 3-thienylmethyl)-4H-p yrrolo[3,2-d]pyrimidin-4-one) in PNP enzyme inhibition assays. In the human MLR, PD 141955 has IC50s of 2.8 and 12.8 muM in the presence and absence, respectively, of 15 muM GdR (means from 10 assays), while th e IC50s of CI-972 tested in parallel are > 30 muM. Concentration-depen dent accumulation of dGTP occurs in PD 141955-treated MLRs under condi tions in which CI-972 lacks detectable activity. Thus, consistent with its greater PNP inhibitory activity in a cell free system, PD 141955 is significantly more potent than CI-972 in its ability to suppress th e MLR.