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.
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.
Voss
Matthew E
ME
Bristol-Myers Squibb Pharmaceuticals, Experimental Station, Rt. 141 & Henry Clay Road, Wilmington, DE 19880-0500, USA.
Carter
Percy H
PH
Tebben
Andrew J
AJ
Scherle
Peggy A
PA
Brown
Gregory D
GD
Thompson
Lorin A
LA
Xu
Meizhong
M
Lo
Yvonne C
YC
Yang
Gengjie
G
Liu
Rui-Qin
RQ
Strzemienski
Paul
P
Everlof
J Gerry
JG
Trzaskos
James M
JM
Decicco
Carl P
CP
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
D019013:CD40 Antigens; D007202:Indicators and Reagents; D007211:Indoles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha