Celecoxib, structure

Organ et al. from York University demonstrated that a diarylated IH-pyrazole-based library, based on the structure of the potent COX II inhibitor Celecoxib [4-(3-trifluoromethyl-5-(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide], could be rapidly prepared using MAOS [59]. Microwave-accelerated Suzuki reaction on 4-(5-iodo-3-methyl-lH-pyrazol-l-yl)-benzenesulfonamide using heterogeneous Pd/C was the principal diversification step investigated (Scheme 41). The interest of the team in microwave... 

Again, detailed structural information at a molecular level was the key. Once these pictures were available slight chemical differences between the COX-1 and COX-2 isoenzymes could be seen COX-2 had a side pocket while COX-1 didn t. This meant that a molecule that could dock into the COX-2 side pocket (binding site) but not into COX-1 would specifically block COX-2 without touching COX-1. In 1999 this hope was realized with the availability of COX-2 selective anti-inflammatories such as Rofecoxib and Celecoxib that can be as much as 50-fold selective for the target. 

The lability of benzylic positions to cytochrome P450 metabolism has been exploited to decrease the unacceptably low clearance and resultant long half-life of various compounds. For example celecoxib, a selective cyclooxygenase inhibitor, has a half-life of 3.5 h in the rat. Early structural leads, represented by compoimds in... 

The crystal structure of the cocrystal formed by celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide) with nicotinamide has been solved from powder X-ray diffraction data [54], The dissolution and solubility of the cocrystal product were found to depend on the medium involved, and a number of the observed phenomena were shown to originate from differences in conversion of the cocrystal celecoxib polymorphic forms I and III. However, through the judicious use of choice excipients, a formulation was developed that took advantage of the crystalline conversion to be up to fourfold more bioavailable than the celecoxib Form-Ill marketed product. 

A close structural analog of the non-selective COX inhibitor diclofenac, lumiracoxib displays a 500-fold greater selectivity for COX-2 than COX-1 in vivo and exhibits a unique pharmacologic profile that includes rapid absorbance and a relatively short plasma half-life (41, 42). Lumiracoxib lacks the tricyclic structure of the diarylheterocycle class of COX-2 selective inhibitors (e.g., celecoxib and rofecoxib) and does not contain a sulfonamide or sulfone group. Although structurally related, lumiracoxib and diclofenac exhibit large differences in the selectivity of COX-2 inhibition, and the molecular basis for this... 

A sulfur component is necessary for the receptor binding of both celecoxib and rofecoxib, but their structures differ and they have different potentials for causing allergic reactions. Consequently, celecoxib is thought to be contraindicated in patients with a history of allergy to sulfonamides. The available data on the immunological tolerability profile of celecoxib and rofecoxib are scanty but merit attention. 

Structures of cyclooxygenase-2 (COX2) selective inhibitors. (A) Celecoxib and (B) Rofecoxib. 

Shih Chen et al. (Columbus, USA) modified the structure of rofecoxib to create compouuds that mimicked the surface electrostatic poteutial of celecoxib, oue of which showed a substantial increase in apoptotic activity." What a challenge for the future ... 

M-Acetylsaccharinyl acid derivatives 408, which are structurally related to COX-2 inhibitor celecoxib, were designed and synthesised [133] from M-saccharinyl acetate 407a, prepared via the reaction of ethyl bromoacetate with sodium saccharin by heating the reactants in DMF (see [133]). Its transformation into the corresponding hydrazide 407b and subsequent reaction with ethyl acetoacetate, /3-diketones and maleic anhydride, afforded the heterocyclic compounds 408 [134] (Scheme 97). 

Nimesulide is a sulfonanilide compound available in Europe that demonstrates COX-2 selectivity similar to celecoxib in whole blood assays. Additional effects include inhibition of neutrophil activation, decrease in cytokine production, decrease in degradative enzyme production, and possibly activation of glucocorticoid receptors. Its structure is ... 

COX-2 Inhibitors Induce Apoptosis with Considerable Differences in Potency. The apoptotic effects of a panel of COX-2-specific inhibitors on human prostate cancer cell lines were evaluated. Table 1 shows that the COX-2 inhibitors, NS398, DuP697, rofecoxib and celecoxib, are similar structurally and with respect to their potencies in COX-2 inhibition (79). In addition, as we reported previously for celecoxib (66), NS398, DuP697, and rofecoxib were capable of inducing apoptosis in both LNCaP and PC-3 cells, as indicated by the characteristic apoptotic features including DNA laddering and caspase-3 (EC 3.4.22.1) activation (Fig. IB and C only data for PC-3 cells is shown). Similarly,... 

Structure-Activity Analysis. As a second approach to further test the h)q)othesis that COX-2 inhibition is not necessary for inducing apoptosis by COX-2 inhibitors, structural modifications of celecoxib were performed to dissociate COX-2 inhibitory and apoptotic activities. Structure-activity analysis was performed by the synthesis of a series of celecoxib derivatives with different substituents at the terminal phenyl ring and evaluation of the apoptosis-inducing potency of each. Figure 9 summarizes the structures, the COX-2 inhibitory activities (ICg(j) and the apoptosis-inducing activities (Tj 2 required for 50% cell death) of celecoxib and seven representative derivatives. 

---