Evolution of Nonsteroidal Anti-Inflammatory Cyclooxygenase (COX) Inhibition and Beyond
P. N. Praveen Rao1 and Edward E. Knaus2.
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. 2Faculty ofPharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Received, April 28, 2008; Revised, August 27, 2008; Accepted, September 3, 2008; Published, September 13, 2008.
ABSTRACT. Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such asrheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such ascyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along withmethods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress hasbeen made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the
last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge. 1. INTRODUCTION The fascinating ability to treat fever and inflammation dates back about 3500 (400 B.C.) years ago to a time when theGreek physician Hippocrates prescribed an extract from willow bark and leaves. Later in the 17th century, the active ingredient of willow bark salicin was identified in Europe. The Kolbe company in Germany started mass producing salicylic acid in 1860. Acetylsalicyclic acid 1 (aspirin) the more palatable form of salicyclic acid was introduced into the market by Bayer in 1899 (1). However, themechanism of action of anti-inflammatory and analgesic agents such as aspirin and indomethacin 2 remained elusive until the early 1960’s. This all changed in the seventies, when John Vane discovered the mechanism of action of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) thereby increasing our ability to develop novel anti-inflammatory therapies (2). The success of NSAIDs intreating various inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) validated inhibition of the enzyme prostaglandin H synthase (PGHS) or cyclooxygenase (COX) as a highly suitable target in anti-inflammatory therapies (3,4). However, the gastrointestinal (GI) toxicities associated with widespread NSAID use proved to be a major drawback during long term therapy (5)....