COX-2 Inhibitors
The design of new anti-inflammatory agents (COX-2 inhibitors) continues to be a tough task due to complexity of the inflammatory process. Production of prostaglandins, the inflammatory mediators depend on the enzyme cyclooxygenases (COX-1 and COX-2). Cyclooxygenases catalyse the oxygenation of biologically active C20 metabolites of arachidonic acid (AA) to produce inflammatory eicosanoids namely, prostaglandins and thromboxane. These key regulatory enzymes facilitate a range of physiological and pathophysiological functions in variety of cells within the body (Blobaum & Marnett, 2007).
The discovery of nonsteroidal anti-inflammatory drugs (NSAIDs) inhibiting prostaglandin synthesis in guinea pig lung and human platelets established COX-1 as an inflammatory target for the ancient class of drugs (Vane, 1971; Smith &Willis, 1971; Ferreria et al. 1971). The subsequent discovery of COX-2 in 1991 during inflammation, recommended that this form of the enzyme signifies the molecular target for the anti-inflammatory effects of NSAIDs (Xie et al., 1991; Fu et al. 1990; Kujubu et al. 1991; Patel et al. 2009). The primary form of COX-1 expressed in the gastrointestinal (GI) tract directed to the search for selective COX-2 inhibitors as potential anti-inflammatory drugs. The new finding of COX-2 inhibitors unveil the reduced GI side effects when compared to gastric side effects exhibited by traditional NSAIDs (Kawai et al. 2005; Al-Hourani et al. 2011; Pairet et al., 1996). As a result, some highly selective COX-2 inhibitors were introduced in the market vizcelecoxib, rofecoxib, valdecoxib, etoricoxib, and lumiracoxib (Prasit & Riendeaue, 1997; Talley, 1999; Talley et al., 1999; Chan et al., 1999; Esser et al., 2005; Marnett et al., 2009). Later on, researchers in United States and Europe conducted long-term placebo-controlled studies that revealed the existence of cardiac side effects in the above cited COX-2 inhibitors. It led to withdrawal of valdecoxib and rofecoxib from the market. These risks until now are assumed to be due to the presence of COX-2 in blood vessels. Later on, it was reported that COX-2 is in fact largely absent in major blood vessels (Ahmetaj-Shala et al., 2015; Hochstrasser, 20017; Liu et al., 2012). This critical information on role of COX-2 in chronic inflammatory disease paved the way to the researchers for rational design of selective COX-2 inhibitors with devoid of cardiovascular and GI events.
On review of literature, abundant information on structural activity relationship of different COX-2 inhibitors was studied. Sing et al. (2004) reported that substitution of methane sulfonamide at various positions of 1, 5-diaryl pyrazole influences the COX-2 inhibiting activity. In particular, introduction of 4-methanesulfonamide group at position-4 of the C-5 phenyl ring of 1, 5-diaryl pyrazoles induced the COX-2 inhibitory activity. This report is on par with the studies of Penning et al., (1997), who found that the most effective COX-2 inhibitor, nimesulide possesses methane sulfonamide group at para position of phenyl ring. Further, Zargi et al (2011) have reported a series of 1,3-diaryl urea and it possess methane sulphonyl functional group at the para position of N-1 phenyl ring and addition of diverse substituents viz -H, -F, -Cl, -Me and -OMe at the para-position of N-3 phenyl ring which enhances COX-2 selective inhibition. During the search of literature, we excavated out that the majority of the research reported so far possess similar pharmacophores with enhanced COX-2 selectivity (Chaudhary et al, 2010; Bali et al, 2012).
The authors of this chapter have taken tyrosine as their core nucleus to design a series of selective COX-2 inhibitors. In this concern, an investigation was made on tyrosine scaffold from the natural sources, since it possesses sterically more complex structure and exhibit advanced binding characteristics compared with synthetic tyrosine compounds (Lahlou, 2013). These quite distinct structural characters may enhance the non-existence of cardiovascular side effects and direct towards COX-2 selectivity. It is found that the complex structures of bioactive dibromotyrosine derivatives obtained from natural sources have proven to possess anti-inflammatory activity (Peng & Hamann, 2005). Therefore, tyrosine scaffolds derived from natural sources are of great interest as candidate COX-2 inhibitor with negligible side effects.
This novel tyrosine skeleton is a proof of principle to be further developed by substituting methane sulphonyl group at p-position of tyrosine moiety along with electron donating groups for enhancing COX-2 inhibiting activity. It is understood from the literature that substitutions of different alkyl, aryl and heteroaryl groups at –OH position of tyrosine nucleus inhibited angiogenesis, growth and development of malignant cells and their migration into the surrounding tissues with negligible toxicity on the living cells (Sallam et al, 2010). It is speculated that substitution of alkyl and aryl groups at –OH position of tyrosine nucleus may eliminate the cardiovascular problems exhibited by COX-2 inhibitors.
Herein, we report how we virtually improved the selectivity of designed tyrosine molecules towards the enzyme COX-2 in order to reduce the risk of cardiovascular events by computational molecular modelling approaches. The section 2 explains various methods adopted in our studies for designing a series of COX-2 inhibitors.