'Bridged' stilbene derivatives as selective cyclooxygenase-1 inhibitors.
Resveratrol ((E)-3,4',5-trihydroxy-stilbene), a phytoalexin found in various plants, shows non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX inhibitors a series of bridged stilbene derivatives was synthesized and evaluated for their ability to inhibit both COX-1 and COX-2 in vitro. The compounds showed a high rate of COX-1 inhibition with the most potent compounds exhibiting submicromolar IC(50) values and high selectivity indices. A prediction model for COX-inhibiting activity was also developed using the classical LIE approach resulting in consistent docking data for our molecule sample. Phenyl substituted 1,2-dihydronaphthalene derivatives and 1H-indene derivatives therefore represent a novel class of highly selective COX-1 inhibitors and land promising candidates for in vivo studies.
Handler
Norbert
N
Department of Medicinal Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
Brunhofer
Gerda
G
Studenik
Christian
C
Leisser
Klaus
K
Jaeger
Walter
W
Parth
Stephanie
S
Erker
Thomas
T
D000818:Animals; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009132:Muscles / Q000187:drug effects*; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes; D013329:Structure-Activity Relationship
D016861:Cyclooxygenase Inhibitors; D007192:Indenes; D009281:Naphthalenes; D013267:Stilbenes; C086079:1,2-dihydronaphthalene; D051545:Cyclooxygenase 1; D000077185:Resveratrol