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.