Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships
Bioorg Med Chem. Apr 15;22(8) doi: /victoryawards.us Epub Mar Structure-activity relationship of celecoxib and rofecoxib for. out to acquire structure-activity relationship data with respect to the point of Cyclooxygenase (COX) inhibitors such as rofecoxib. 1 (1), celecoxib 2 (2), . Analyses were performed for C, H and N (Micro- analytical Laboratory. Apr 15, Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously.
Medical uses[ edit ] Celecoxib is used for osteoarthritisrheumatoid arthritisacute painmusculoskeletal painpainful menstruationankylosing spondylitisand to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis.
NSAIDs are associated with an increased risk of serious and potentially fatal adverse cardiovascular thrombotic events, including myocardial infarction and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Individual cardiovascular risk profiles should be evaluated prior to prescribing.
New-onset hypertension or exacerbation of hypertension may occur NSAIDs may impair response to thiazide or loop diureticsand may contribute to cardiovascular events; monitor blood pressure and use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema or heart failure.
Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternative therapies should be considered for patients at high risk.
These events may occur at any time during therapy and without warning. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk.
Anemia may occur; monitor hemoglobin or hematocrit in people on long-term treatment. Celecoxib does not usually affect prothrombin timepartial thromboplastin time or platelet counts; it does not inhibit platelet aggregation at approved doses. Despite their grand commercial success, rofecoxib and valdecoxib were withdrawn recently due to its adverse cardiovascular side effects8 raising concerns regarding the safety of other coxibs.
Interestingly, celecoxib, the first drug launched in the market is still in patient's use and it seems that there are perhaps striking differences among various COX-2 inhibitors concerning cardiovascular risk. However, it has been reported that some of the coxibs possessing sulfonamide moiety can inhibit carbonic anhydrase II. The diaryl or aryl-heteroaryl ethers and thioethers are also known to be selective inhibitors of COX This class of COX-2 inhibitors Figure 1 includes N- 4-nitrophenoxy phenyl methanesulfonamide or nimesulide 1NS 2flosulide 3and L, 4.
It was observed that when the electron withdrawing group was incorporated in the form of conformationally restricted cyclic ketones see 3 and 4, Figure 1 and lactones see 5, 6 and 7, Figure 1 some of them showed better COX-2 inhibiting properties and improved oral bioavailability. We therefore, became interested in attaching the EWG one atom away from the C-4 position and to study its subsequent effect on COX inhibition.
Additionally, while the replacement of methyl group of NHSO2CH3 of nimesulide by a trifluoromethyl CF3 moiety has been reported,16 the role of acidic NH of methane sulfonamide moiety on anti-inflammatory activities, however, has not been studied extensively.
There was a problem providing the content you requested
Considering all these aspects and in continuation of our research on the development of novel anti-inflammatory agents we have prepared a number of chemically modified derivatives of nimesulide some of which showed interesting COX inhibiting properties. The synthesis of N-acylated compounds of nimesulide 9a-b is shown in Scheme 1. The structure of all compounds synthesized was confirmed by spectroscopic methods. The synthesis of N-acylated compounds 11ag is shown in Scheme 2.
N- 4-aminophenoxy phenyl methanesulfonamide 10, a reduced form of nimesulide 1 was efficiently prepared from N- 4-nitrophenoxy phenyl methanesulfonamide nimesulide 1 by using Sn and HCl. The amino group of 10 was found to be highly reactive towards acylation and arylsulfonation reaction.
Thus compound 10 was converted to the corresponding acylated or arylsulfonated derivative easily at room temperature as shown in Scheme 2. Results of our acylation and arylsulfonation reaction are listed in Table 1. As indicated in Table 1 that acylation of nimesulide requires longer reaction time and higher temperature than its reduced form 10 entries vs. These reactions were normally completed within min irrespective of the acyl chlorides used entriesTable 1.
Chemical modifications of nimesulide
Yields of products were also found to be excellent when arylsulfonyl chlorides were reacted with 10 entries 10 and 11, Table1. In the IR spectra of all the compounds carbonyl-stretching bands of amide was seen in the region of cm Many of these compounds were tested against cyclooxygenase enzyme in vitro18 and all of them showed inhibitory effects especially against COX The moderate COX-2 selectivity shown by 11d and 12a could be beneficial as this might lead to the identification of COX-2 inhibitors with better safety profile.
Overall, the present study indicated that a new class of diaryl ethers could be generated via chemical modifications of nimesulide without affecting their COX inhibiting properties and COX-2 selectivity could be modulated via proper modifications.
Mechanistically, the acylation of nimesulide proceeds via generation of an anion from the methansulfonamide moiety i. This anion generation is facilitated due to the resonance stabilization of the resulting anion caused by the electron withdrawing nitro group. A further acylation or sulfonylation was not observed in case of 11 or 12 respectively due to the lack of resonance stabilization of the anion generated in these cases compared to that of nimesulide.
Conclusions In conclusion we have described design and synthesis of a number of diaryl ether derivatives of potential biological significance via chemical modifications of a commonly used anti-inflammatory agent nimesulide.
A variety of N-acylated and N-sulfonylated derivatives of 10 were conveniently prepared for the first time in good to excellent yields. Some of the compounds synthesized showed moderate selectivity for COX-2 inhibition over COX-1 when tested against cyclooxygenase enzyme in vitro.
Experimental General methods Reactions were monitored by thin layer chromatography TLC on silica gel plates 60 Fvisualizing with ultraviolet light or iodine spray.