Pyrrolo[3,2-d]pyrimidines, a new class of purine nucleoside phosphorylase (PNP) inhibitors as potential T-cell selective immunosuppressive agents.

Previously, we have described the synthesis and biological activity of 2,8-diamino-1,9-dihydro-9-(2-thienylmethyl)-6H-purin-6-one (PD 119229; Cl-950) as a potent and competitive PNP inhibitor. As a part of our continuing efforts to develop a PNP inhibitor for autoimmune diseases, we have synthesized a series of pyrrolo[3,2-d]pyrimidines as PNP inhibitors. In this series, 2,6-diamino-3,5-dihydro-7-(3- thienylmethyl)-4H-pyrrolo-[3,2-d]pyrimidin-4-one (Cl-972) was found to be a potent, competitive inhibitor of PNP with Ki of 0.83 microM. It was also found to be selectively cytotoxic to human MOLT-4 (T cell) (IC50 = 3.0 microM) but non-toxic to MGL-8 (B cell) lymphoblasts. Cl-972 is under development as a potential T-cell selective immunosuppressive agent. Synthesis and biological activities of the series are discussed.