The Treatment Of Osteoarthritis

Published Date: 02 Nov 2017

Arachidonic acid’s biotransformation via the LOX (lipoxygenase) and COX pathways lead to the production of the inflammation meditator family known as the Eicosanoids. The enzyme cyclooxygenase which occurs as two isoforms: COX-1 and COX-2, is involved in the production of prostaglandins as part of the rate limiting step. Rofecoxib and other selective COX-2 inhibitors showed promise and hope in chemoprevention without NSAIDs side effects (gastrointestinal) and aspirin (bleeding risk). The COX pathway is where thromboxanes, prostaglandins and prostacyclin (prostanoids) are made whereas LTs (leukotrienes) are produced via the LOX pathway. LTs can be produced via the 15-LOX isoenzyme and 5-LOX. The 15-LOX has been linked with cardiovascular events such as atherosclerosis with its involvement in the oxidative alteration of LDLs (low-density lipoproteins). Also during the COX blockade there is an up-regulation of the 5-LOX pathway.

This means that within the Arachidonic acid cascade a synergistic block of both the LOX and COX pathways can produce a better anti-inflammatory efficacy by the action of dual inhibitors of LOXs and COXs. This represents a substitute to selective COX-2 inhibitors which is safer and more favourable.C:\Users\WajidB\rofecoxibpicessay.jpg

An example of a dual inhibitor is Licofelone (3 - in diagram 1) which has less GI toxicity as opposed to standard NSAIDs and is used in the treatment of osteoarthritis. Inhibitors like 4 (in diagram 1) were designed looking at N-hydroxyurea and hydroxamic acid based selective 5-LOX inhibitors. Inhibitor 4 has the 5-LOX hydroxamic acid moiety which is an iron chelator and COX-2 diarylpyrazole moiety.

More recently Rofecoxib had been looked at to be coupled with an N-hydroxycarbamate moiety (showed inhibitory actions towards 5-LOX) or an oxime group (able to bind metal ions in various modes). Experimental data from in-vivo analgesic and anti-inflammatory, and in-vitro inhibition of the enzyme has shown that the addition of a para-oxime moiety to the phenyl ring of rofecoxib on the C-3 produces an appropriate template to make the LOX and COX dual inhibitors. The data also showed that analgesic and oral anti-inflammatory activity was shown by the 5-LOX/15-LOX and COX-2 dual inhibitors i.e. 6a and 5a that could show a clinical relevance. Also it was seen that a combination of an optimal inhibitory action against 5-LOX/15-LOX and COX-2 was shown by the 5a oxime compound. 6a showed inhibitory action against 5-LOX and COX-2 which was effective.

Another study concluded that a higher anti-inflammatory activity was shown by certain derivatives of novel acrylic acid. Many of them demonstrated in a range of experimental tests good anti-oxidant properties, inhibitory action against in-vitro soybean LOX and lipid peroxidation; they also showed to be potent with respect to -OH. The anti-inflammatory activity in-vivo was proved to be good from the compounds tested which showed in-vitro high anti-radical activity. The hydrophobic interactions of the more potent compounds were the reason for the inhibitory action. These compounds also attached effectively to the inhibited enzyme’s active site.

Compounds 7 and 8 showed significant COX-1 and LOX inhibition activity, a high anti-oedematous action with an impressive anti-inflammatory activity. Also they showed a respectable activity against hydroxyl radicals. This particular dual inhibition could result reduced inflammation along with a protective influence as the unwanted side-effects are usually seen with the COX-1 inhibition activity. Nonetheless, the LOX and COX-1 enzyme inhibition was not very high. 7 8http://ars.els-cdn.com/content/image/1-s2.0-S0223523410007762-fx6.jpghttp://ars.els-cdn.com/content/image/1-s2.0-S0223523410007762-fx4.jpg

Other compounds were created that may help start the development of anti-inflammation therapeutic agents that more potent. The initial COX and LOX active site docking studies was said to be helping in future designs and they were to also use this to look into the studied compounds’ anti-phlogistic action mechanism.

In a more recent study COX-2 inhibitory action was found in a new series of pyrimidines (structure 9). The experimental results gathered regarding the COX-2 in-vitro inhibition showed that the groups present on the pyrimidine ring on the C-2, 4 and 6 positions were the cause of how selective and potent the inhibitory action was.

Selectivity and potency of diverse grades in COX-2 inhibitors were obtained when the optimal and suitable combination of groups/substituents were in the C-2, 4 and 6 position. Several of the compounds tested were found to have a considerably higher selectivity and/or potency compared to Rofecoxib. As a summary of the ideal substituents, SI and IC50 of HWB COX-2 were optimal for pyrimidines (9) when R5 was ideally H (as a substituent was more steric hindrance was unfavourable to selectivity and potency), R4 was Cl, CF3, iPr or alkoxy, R1 was Me, X[CH(R3)]nR2 with R2 being either 4-methyphenyl, 4-fluorophenyl, 3-thiophenyl, 2-thiophenyl or phenyl.

One of the best results in terms of potency for COX-2 inhibition from the data compared to Rofecoxib was shown by compound 10. The diagram below shows the assays for HWB – Human purified blood (b) and PE – in-vitro purified enzyme (a), the results was 1.2nM for HWB COX-2 IC50. Compound 10 had a higher selectivity of 780-fold compared to Rofecoxib with a value of 81,300 for the HWB selectivity index, this made it the pyrimidine derivative with the most selectivity.

It was seen that for the inhibitory selectivity and potency of COX-2 to be optimum a substitution was required at one of the aryl rings by SO2Me or para-SO2NH2. It is well-known for these two polar groups to insert themselves into the COX-2 binding site’s secondary pocket (not seen in COX-1) and induce selectivity of COX-2. The HWB assay showed SO2Me to have the best selectivity and potency profile and hence it was the chosen polar group to be included into the pyrimidines.