title: Novel inhibitors of the nuclear factor of activated T cells (NFAT)-mediated transcription of beta-galactosidase: potential immunosuppressive and antiinflammatory agents.
abstract: The preparation of a series of quinazoline-2,4-diones, 1-3, and pyrrolo[3,4-d]pyrimidine-2,4-diones, 4-8 is described. A small number of quinazolinedione analogs were identified from random screening to possess low micromolar (1.3-4.4 microM) potency in the nuclear factor of activated T cells-1-regulated beta-galactosidase expression assay. An expanded analog search resulted in identifying pyrrolopyrimidinedione 4b which is 5-10-fold (0.26 microM) more potent than the quinazolinediones. Replacement of the benzyl group with naphthyl led to greater potency and conformationally restricted analogs 4u-w. The naphthyl and acenaphthyl analogs are 10-100 times more potent inhibitors of beta-galactosidase expression than 4b. Binding affinity data for displacement of radiolabeled 4s from Jurkat cell membranes reflected an excellent correlation with the IC50 value for inhibition of beta-galactosidase activity. These products, whose structure-activity relationships are discussed, are of interest as potential agents for preventing interleukin-2 gene transcription.
authors.affiliation: Department of Biochemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426, USA.
authors.forename: W F
authors.initials: WF
authors.lastname: Michne
authors.forename: J D
authors.initials: JD
authors.lastname: Schroeder
authors.forename: J W
authors.initials: JW
authors.lastname: Guiles
authors.forename: A M
authors.initials: AM
authors.lastname: Treasurywala
authors.forename: C A
authors.initials: CA
authors.lastname: Weigelt
authors.forename: M F
authors.initials: MF
authors.lastname: Stansberry
authors.forename: E
authors.initials: E
authors.lastname: McAvoy
authors.forename: C R
authors.initials: CR
authors.lastname: Shah
authors.forename: Y
authors.initials: Y
authors.lastname: Baine
authors.forename: D G
authors.initials: DG
authors.lastname: Sawutz
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects*; D001616:beta-Galactosidase / Q000235:genetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D001616:beta-Galactosidase