Bioorganic & Medicinal Chemistry Letters 9 (1999) 1773-1778 Pergamon BIOORGANIC & MEDICINAL CHEMISTRY LETIERS THE DISCOVERY OF ROFECOXIB, [MK 966, VIOXX ®, 4-( 4'-METHYLSULFONYLPHENYL)-3-PHENYL-2(5H)-FURANONE], AN ORALLY ACTIVE CYCLOOXYGENASE-2 INHIBITOR P. Prasit,* Z. Wang,* C. Brideau, C.-C. Chan, S. Charleson, W. Cromlish, D. Ethier, J.F. Evans, A.W. Ford- Hutchinson, J.Y. Gauthier, R. Gordon, J. Guay, M. Gresser, S. Kargman, B. Kennedy, Y. Leblanc, S. L~ger, J. Mancini, G.P. O~Neill, M. Ouellet, M.D. Percival, H. Perrier, D. Riendeau, I. Rodger, P. Tagari, M. Th~rien, P. Vickers, E. Wong, L.-J. Xu, R.N. Young, and R. Zamboni Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Qudbec HgR 4P8, Canada S. Boyce and N. Rupniak Merck Research Laboratories, Harlow, Essex, UK M. Forrest and D. Visco Merck Research Laboratories, RatTway, NJ 07065, U.S.A. D. Patrick Merck Research Laboratories, West Point, PA 19486, U.S.A. Received 1 April 1999; accepted 6 May 1999 Abstract: The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx®) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition. © 1999 Publishedby ElsevierScienceLtd. All right.s reserved. All currently available nonsteroidal antiinflammatory drugs (NSAIDs) have been characterized as dual COX-I/COX-2 inhibitors, l The most notable adverse effect with existing NSAIDs is the increased risk of gastrointestinal ulceration, perforation and hemorrhage, which has been associated with the inhibition of COX-17 It is now generally accepted that a COX-2 inhibitor would have the potential to be a potent antiinflammatory agent without the toxicity associated with nonselective NSAIDs. 3 Free of dose-limiting COX-l-associated toxicity, a COX-2 inhibitor may therefore demonstrate comparable or possibly superior clinical efficacy to existing NSAIDs for a variety of clinical disorders. The improved safety profile of cox-2 inhibitors may allow the use of these new agents for long-term prophylactic use in otherwise healthy individuals with a known genetic susceptibility to certain chronic diseases. Of particular interest is the detection of COX-2 in colorectal carcinoma tissues4 and the demonstration that COX-2 inhibition reduces the number of polyps in the ApcA716"/" knockout mice (a model of human familial adenomatous polyposis)5 and suppresses colonic aberrant crypt foci. 6 This suggests that COX-2 plays a key role in polyp formation and provides the basis for chemopreventive treatment ofpolyposis and cancer by selective COX-2 inhibitors.7 The Baltimore Longitudinal Study of Aging, with 1686 participants, reported in 1997 that the risk of developing Alzheimer's disease is reduced among NSAIDs users, especially those who have taken the medications for two years or more. 8 No 0960-894X/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved. PH: S0960-894X(99)00288-7