Biochemical and Pharmacological Properties of CI-972, a Novel 9-Deazaguanine Analog Purine Nucleoside Phosphorylase (PNP) Inhibitor

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Abstract
CI-972 (2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one monohydrochloride, monohydrate) is a novel inhibitor of PNP (Ki = 0.83 μM) under development as a T cell-selective immunosuppressive agent. CI-972 inhibited proliferation (3H-thymidine uptake) of human MOLT-4 (T cell) but not MGL-8 (B cell) lymphoblasts with respective IC50s of 3.0 and >50 μM when tested with 10 μM 2′-deoxyguanosine. Without addition of exogenous 2′-deoxyguanosine, CI-972 was not inhibitory to any human T or B lymphoblastoid cell line tested. 2′-Deoxycytidine (10 μM), but not hypoxanthine or adenine, restored MOLT-4 cell growth. Inhibition of 3H-thymidine uptake in MOLT-4 cells correlated with accumulation of dGTP, while alterations in guanine nucleotides were not observed. 2′-Deoxycytidine (10 μM) also blocked dGTP accumulation in MOLT-4 cells. CI-972 showed activity in vivo over a broad dose range: At 5–150 mg/kg p. o., CI-972 produced dose-dependent elevation of plasma inosine one hr after administration to rats (mean maximum of 2.62 vs. 0.06 μM in controls). Guanosine was also significantly elevated in a concentration-dependent manner, although the effect was not as impressive. Plasma nucleosides remained statistically-significantly elevated for up to four hr following a single oral dose of CI-972.