title: Both 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones and 3-thioxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-ones are light-dependent tumor necrosis factor-alpha antagonists.
abstract: Based on the realization that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones are tumor necrosis factor-alpha antagonists, we discovered two additional classes of antagonists: 3-thioxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-ones (via rational design) and 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (via computer-guided screening). Chemical modification of the lead structures showed that the structure-activity relationship profiles for both of these series were dependent on the electronic properties of the molecules. Subsequent studies showed that they were light-dependent inhibitors.
authors.affiliation: Bristol-Myers Squibb Pharmaceuticals, Experimental Station, Rt. 141 & Henry Clay Road, Wilmington, DE 19880-0500, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Voss
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Brown
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
authors.forename: Meizhong
authors.initials: M
authors.lastname: Xu
authors.forename: Yvonne C
authors.initials: YC
authors.lastname: Lo
authors.forename: Gengjie
authors.initials: G
authors.lastname: Yang
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Strzemienski
authors.forename: J Gerry
authors.initials: JG
authors.lastname: Everlof
authors.forename: James M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D004563:Electrochemistry; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008027:Light; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000528:radiation effects
chemical_list: D019013:CD40 Antigens; D007202:Indicators and Reagents; D007211:Indoles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha