Development of COX-2 Selective Inhibitors - Therapeutic Perspectives

Abstract

Aspirin and conventional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed for the treatment of musculoskeletal disorders with a major dose limiting gastrointestinal toxicity. However the discovery of inducible second isozyme of cyclooxygenase-2 (COX-2) opened up a new era in therapeutics. The selective COX-2 inhibitors have emerged as a class of compounds for the treatment of inflammatory disorders based on the molecular knowledge, characterization of two distinctive isozymes namely the constitutive cytoprotective cycloooxygenase-1 (COX-1) and the inducible inflammatory COX-2.The current hypothesis is that anti-inflammatory effects are mediated through the inhibition of COX-2 derived inflammatory prostaglandins (PGs), on the contrary the gastrointestinal adverse effects were due to inhibition of constitutive COX-1. The rationale approach is that the selective COX-2 inhibitors may provide a significantly improved gastrointestinal risk-benefit ratio over NSAIDs. However, the withdrawal of Vioxx by Merck & Co from worldwide markets has triggered a debate on the safety of this class as it was observed, that selective inhibition of COX-2 could lead to an imbalance of normal homeostasis resulting in potential cardiovascular risks. Evidence is emerging that the constitutively expressed COX-2 has important role in gastric mucosal protection, renal and the cardiovascular homeostasis. Suppression of endothelial prostacyclin (PGI 2) by highly selective COX-2 inhibitors could lead to myocardial infarction and stroke implicating that COX-2 may have a pivotal role under certain physiological conditions.

Orthodontic tooth movement after different coxib therapies

“…These results, based on animal protocols, shortterm duration, and high-intensity forces, need to be confi rmed and re-evaluated under other experimental conditions, on other species including humans. The debate regarding coxib substances and safety issues will probably evolve; eventually it will lead to the introduction of new anti-infl ammatory substances ( Casturi et al , 2005 ).…”

Application of per-residue energy decomposition to identify the set of amino acids critical for in silico prediction of COX-2 inhibitory activity

“…This led to adverse GI toxicities [ 10 , 11 , 12 ]. In order to develop better anti-inflammatory inhibitors with minimum adverse effects, efforts were made by various research communities for the development of selective COX-2 inhibitors [ 13 , 14 , 15 ]. The structural differences between COX-1 and COX-2 at the active site were exploited [ 16 ] for the same.…”

Update on COX-2 Selective Inhibitors: Chemical Classification, Side Effects and their Use in Cancers and Neuronal Diseases

“…34). Cyclooxygenase Inhibitor-Nitric Oxide Donors (CINODS) [155] were synthesized by modifying coxibs with introduction of a NO-donor group and displayed a reduced cardiovascular risk compared to selective COX-2 compounds [156][157][158][159][160][161][162][163][164]. Since NO and H 2 S act in concert for the maintenance of gastric mucosa, dual H 2 S-NO releasing compounds were also elaborated [156,165] (compounds 372 g-j, see Table 99) (Fig.…”

“…However, these findings and the involvement of COX-2 inhibition in GI damages remain controversial [164,174]. Despite the relative low rate of GI side effects associated with selective COX-2 inhibitors such as coxibs in several clinical studies [160,161,175,176], efforts are still made to enhance GI tolerability of AINS. The current solutions include the use of NSAIDS or coxibs in combination with proton-pump inhibitor [177,178], and the development of new drugs with NO or H2S releasing parts added to the structure of known NSAIDS.…”