Inhibitors of cyclooxygenase COX

Aspirin, acetaminophen, and many other nonsteroidal anti-inflammatory drugs (e.g., Advil) are inhibitors of cyclooxygenase, COX. 

Aspirin (4.16) is an irreversible inhibitor of cyclooxygenase (COX), an enzyme involved in the synthesis of prostaglandins, a family of hormones (Scheme 4.15). The acetyl group in aspirin is transferred to the OH of Ser530 in the active site of COX-1. The mode of inhibition of COX-2, an isoform of COX-1, by aspirin is similar.15... 

Ibuprofen works by inhibiting the enzyme cyclooxygenase (COX), which in turn interferes with the synthesis of prostaglandins. COX exists as several coenzyme forms that are similar in structure COX-1, COX-2, COX-3 ibuprofen is a nonselective inhibitor of both COX-1... 

Talley, J. J. Selective Inhibitors of Cyclooxygenase-2 (COX-2). Progress in Medicinal Chemistry - Vol. 

Talley JJ (1999) Selective inhibitors of cyclooxygenase-2 (COX-2). Prog Med Chem 36, 201-234. 

Filipponi et al. [7] studied the differences in the active sites of the two isoforms of cyclooxygenase (COX), an enzyme involved in the biosynthesis of pro-inflammatory prostaglandins. Two isoforms of COX exist a constitutive cyclooxygenase-1 and an inducible cyclooxygenase-2, and it is believed that COX-2 selective inhibitors provide anti-inflammatory agents with a superior safety profile [35]. 

The search for specific inhibitors of cyclooxygenase has opened a new area of research in this field. This cnr.ynic occurs in two forms, cyclooxygenase I (COX-I) and cyclooxygenase 2 (COX-2). COX-1 is a constitutive cn/yme and plays a role in the production of essential prostaglandins. Inhibition of this cn/.yme by all the older, nonsclective NSAIDs is priinurily responsible for a number of their side effects. The COX-2 enzyme is induced in response to the release of several proinflammatory mediators, leading to the inflammatory response and pain. Thus, there was an active search for specific inhibitors of the COX-2 cn/.yme. This has been successful with the approval of three COX-2 inhibitors. discus.sud below. 

FIGURE 33-4. Tissue distribution and actions of cyclooxygenase (COX) isoenzymes. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin (ASA) inhibit COX-1 and COX-2 to varying degrees COX-2 inhibitors inhibit only COX-2. Broken arrow indicates inhibitory effects. 

Most NSAIDs are nonselective inhibitors of cyclooxygenases, acting on both COX 1 and COX 2 isoforms to decrease formation of PGs and thromboxanes. This action is a primary (but not sole) contributor to the pharmacologic actions of NSAIDs. These actions include analgesic, antipyretic, anti-inflammatory, and antiplatelet effects. Acetylsalicylic acid (ASA) is the prototype of the group, which includes more than 20 individual drugs. 

Most NSAIDs are nonselective inhibitors of cyclooxygenases, acting on both COX 1 and COX 2 isoforms to decrease formation of PCs and thromboxanes. 

Pyrrolinones are important synthons in the preparation of many important compounds including amino acids, various alkoids and many natural products. These heterocyclic derivatives have also been shown to express anti-tumor properties. In addition, they are inhibitors of cyclooxygenase-2 (COX-2), and HIV-1 protease. They also possess several important and exploitable medicinal properties. Pyrrolinones can be synthesized from functionalized imino-alkynes via cyclohhydrocarbonylation in the presence of a zwitterionic rhodium catalyst (ZW) 106 with both high regioselectivity and chemoselectivity as well as in good overall yield (Table 2-3). This versatile reaction system allows for easy access to important synthons. ... 

More than 15 years ago, Jimg et aL reported the synthesis of the dicobalthex-acarbonyl derivative 31 (Q)-ASS) of the well-known analgesic aspirin (acetylsali-cylic acid (ASS)) [107]. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ASS are known to bind to cyclooxygenases (COXs). This family of enzymes is responsible for the formation of prostaglandin H2 from arachidonic acid. Three subtypes of COX are known, namely COX-1, COX-2, and COX-3, which is a splice variant of COX-1. COX-1 is constitutionally expressed, while COX-2 is overexpressed in many cancer cell lines. ASS is a selective inhibitor of the COX-1 subtype and its analgetic and antiaggregating effects stem from this interaction. 

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