title: Pyrrolo[3,2-d]pyrimidines, a new class of purine nucleoside phosphorylase (PNP) inhibitors as potential T-cell selective immunosuppressive agents.
abstract: 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.
authors.affiliation: Parke Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: J C
authors.initials: JC
authors.lastname: Sircar
authors.forename: C R
authors.initials: CR
authors.lastname: Kostlan
authors.forename: R B
authors.initials: RB
authors.lastname: Gilbertsen
authors.forename: M K
authors.initials: MK
authors.lastname: Dong
authors.forename: W A
authors.initials: WA
authors.lastname: Cetenko
mesh_terms: D002460:Cell Line; D004912:Erythrocytes / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000097:blood; D011743:Pyrimidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D011743:Pyrimidines; D013876:Thiophenes; C070377:CI 972; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase