Inhibitors of human purine nucleoside phosphorylase. Synthesis of pyrrolo[3,2-d]pyrimidines, a new class of purine nucleoside phosphorylase inhibitors as potentially T-cell selective immunosuppressive agents. Description of 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d] pyrimidin-4-one

J Med Chem. 1992 May 1;35(9):1605-9. doi: 10.1021/jm00087a015.


Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme in the purine cascade and has been a target for drug design for sometime. A series of potent human PNP inhibitors, pyrrolo[3,2-d]pyrimidines (9-deazaguanines), has been synthesized and evaluated in the enzyme assay and in the cell line assay using MOLT-4 (T-cell) and MGL-8 (B-cell) lymphoblasts for selectivity. One of the compounds, 2,6-diamino-3,5- dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidine-4-one (11c; CI-972), was found to be moderately potent, competitive, and reversible inhibitor of PNP with Ki = 0.83 microM. It was also found to be selectively cytotoxic to MOLT-4 lymphoblasts (IC50 = 3.0 microM) but not to MGL-8 lymphoblasts and was evaluated further. Compound 11c (CI-972) is under development in the clinic.

MeSH terms

  • B-Lymphocytes / drug effects
  • Erythrocytes / enzymology
  • Humans
  • Immunosuppressive Agents / chemical synthesis
  • Immunosuppressive Agents / pharmacology*
  • Kinetics
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • T-Lymphocytes / drug effects*
  • Thiophenes / chemical synthesis
  • Thiophenes / pharmacology*


  • Immunosuppressive Agents
  • Pyrimidines
  • Thiophenes
  • CI 972
  • Purine-Nucleoside Phosphorylase