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.
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.
Sircar
J C
JC
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Kostlan
C R
CR
Gilbertsen
R B
RB
Bennett
M K
MK
Dong
M K
MK
Cetenko
W J
WJ
D001402:B-Lymphocytes / Q000187:drug effects; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D011743:Pyrimidines; D013876:Thiophenes; C070377:CI 972; D011683:Purine-Nucleoside Phosphorylase