NOVEL INHIBITORS OF THE NUCLEAR FACTOR OF ACTIVATED T-CELLS (NFAT)-MEDIATED TRANSCRIPTION OF BETA-GALACTOSIDASE - POTENTIAL IMMUNOSUPPRESSIVE AND ANTIINFLAMMATORY AGENTS

The preparation of a series of quinazoline-2,4-diones, 1-3, and pyrrol o[3,4-d]pyrimidine-2,4-diones, 4-8 is described. A small number of qui nazolinedione analogs were identified from random screening to possess low micromolar (1.3-4.4 mu M) potency in the nuclear factor of activa ted T cells-1-regulated beta-galactosidase expression assay. An expand ed analog search resulted in identifying pyrrolopyrimidinedione 4b whi ch is 5-10-fold (0.26 mu M) more potent than the quinazolinediones. Re placement of the benzyl group with naphthyl led to greater potency and conformationally restricted analogs 4u-w. The naphthyl and acenaphthy l analogs are 10-100 times more potent inhibitors of beta-galactosidas e expression than 4b. Binding affinity data for displacement of radiol abeled 4s from Jurkat cell membranes reflected an excellent correlatio n with the IC50 value for inhibition of beta-galactosidase activity. T hese products, whose structure-activity relationships are discussed, a re of interest as potential agents for preventing interleukin-2 gene t ranscription.