Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

Abstract

ABSTRACT. Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid 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 as cyclooxygenase (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-2 inhibitors, 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 with methods 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 has been 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.

Construction and Optimization of Structure-Based Virtual Screening Protocols to Identify Cyclooxygenase-1 Inhibitors Using Open Babel, Spores and Plants

“…Those NSAIDs are inhibiting cyclooxygenase (COX) enzyme from converting arachidonic acid (AA) to prostaglandin (PG) H and in turn inhibiting the inflammation processes [1,2]. In early 90's, Masferrer et al [2][3] discovered that COX consists of two isoforms, which were subsequently called cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is constitutively expressed and it is believed that inhibiting the constitutive enzyme COX-1 can lead to gastrointestinal (GI) toxicities [2,4].…”

“…In early 90's, Masferrer et al [2][3] discovered that COX consists of two isoforms, which were subsequently called cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is constitutively expressed and it is believed that inhibiting the constitutive enzyme COX-1 can lead to gastrointestinal (GI) toxicities [2,4]. Moreover, COX-2 is induced when inflammation processes occurred [2,4].…”

“…COX-1 is constitutively expressed and it is believed that inhibiting the constitutive enzyme COX-1 can lead to gastrointestinal (GI) toxicities [2,4]. Moreover, COX-2 is induced when inflammation processes occurred [2,4]. This has led to the hypothesis that COX-1 is involved in the antiinflammatory processes while COX-2 in the proinflammatory processes [2,4].…”

“…Moreover, COX-2 is induced when inflammation processes occurred [2,4]. This has led to the hypothesis that COX-1 is involved in the antiinflammatory processes while COX-2 in the proinflammatory processes [2,4]. Designing compounds that selectively inhibit COX-2 has then become attractive to academia and pharmaceutical industries and led to blockbuster drugs (celecoxib (Celebrex TM ) and rofecoxib (Vioxx TM )) that achieve sales more than one billion US dollars within 15 months post launch [2].…”

“…This has led to the hypothesis that COX-1 is involved in the antiinflammatory processes while COX-2 in the proinflammatory processes [2,4]. Designing compounds that selectively inhibit COX-2 has then become attractive to academia and pharmaceutical industries and led to blockbuster drugs (celecoxib (Celebrex TM ) and rofecoxib (Vioxx TM )) that achieve sales more than one billion US dollars within 15 months post launch [2]. Notably, after 5 years from its launch, rofecoxib (and followed by valdecoxib (Bextra TM ) has been withdrawn from the market due to its adverse cardiovascular events [2].…”