PF-4693627: Potential New Anti-Inflammatory Agent Development And Significance

Current Anti-Inflammatory Agents and Their Limitations

The drug PF-4693627 has been under research as one of the next potential safe, potent and more bioavailable anti-inflammatory agent, with a mechanism of action different from the current textbook anti-inflammatory agents. This report presents the details of its development and assesses whether it’s up to the task or not.  Current anti-inflammatory agents such as Nonsteroidal anti-inflammatory agents (NSAIDS) and corticosteroids have been used for this purpose for some time now. However, they pose many side effects. Corticosteroids have undesirable immunosuppressive side effects making patients susceptible to other opportunistic diseases. They can also cause osteoporosis, a bone disease.  NSAIDs cause gastrointestinal disturbances, and more specifically, predispose to formation of ulcers and liver parenchymal destruction. The two classes of agents listed above inhibit inflammation by inhibiting the cyclooxygenase enzymes and phospholipase enzymes respectively. This displays an urgent need for a better and safer drug for inflammation.

The agents above pose the side effects because of blocking enzymes higher in the inflammatory pathway inhibiting the formation of compounds that are also required for normal body functions. For example, NSAIDs inhibit the formation of several prostaglandins, which are required for the production of substances such as Mucus that protects the stomach wall, leading to a predisposition to ulcers. Microsomal prostaglandin E synthase-1 (mpges-1) inhibitors present better safety compared to existing anti-inflammatory agents. This is because they are more specific, due to inhibition of formation of only one specific prostaglandin E₂. Back in 2001, scientists reported the first ever mpges-1 synthetic inhibitor. Since then, many such compounds with different structures have been developed. However, only two inhibitors of this enzyme have gone into clinical trials though none is on the market yet. PF-4693627 is one the two agents.

More studies are being carried out since luckily these agents have anticancer activity too. This essay presents a discussion of the findings from the studies carried out on PF-4693627 and the significance of the same findings in addressing inflammation basing on the article: Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012). An explanation of the stage of drug development the drug PF-4693627 had reached the time article was written is discussed. The progress that has been made with the drug since the publication and a proposition of the next steps or experimental results that are required to take the drug to the next stage of the drug development pathways are presented.   

In the article: Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), an array of benzoxazoles as inhibitors of microsomal prostaglandin E synthase 1 with excellent selectivity and potency, with unparalleled bioavailability are discussed. The benzoxazole chain has been cited in several patent literatures as being able to yield potent compounds with activity against a class of enzymes, which includes the mpges-1. Prostaglandin E₂ is a vital mediator if inflammation, both acute and chronic. It also mediates fever and pain. It’s found among other places, the synovial fluid in patients with osteoarthritis and rheumatoid arthritis. Breakdown of prostaglandin E₂ is initiated by breakdown of arachidonic acid by phospholipase A₂ from membrane phospholipids. This is then converted to prostaglandin H₂ by enzyme cyclooxygenase and by prostaglandin E synthase to prostaglandin E₂.

Microsomal Prostaglandin E Synthase-1 Inhibitors

There are three forms of prostaglandin E synthases (PGES): Microsomal pges-1, cytosolic pges, and microsomal pges-2.  Both cytosolic pges and microsomal pges-2 are expressed constitutively expressed in many tissues hence their blockage would lead to a number of side effects depending on the tissues affected. Microsomal pges-1, referred in this report as mpges-1 is only upregulated during inflammation. Selective inhibition of this enzyme would, therefore, lead to inhibition of prostaglandin E₂ production only under inflammatory conditions while sparing other constitutive mediators such as prostacyclin and thromboxane.   

Initially, literature had described a series of selective and more potent mpges-1 inhibitors that were represented by 1. 1 was obtained by optimizing yet another compound, FLAP (5-lipoxygenase-activating protein) inhibitor lead. It had moderate human mpges-1 and rat mpges-1 inhibition. However, this couldn’t be reproduced in vivo, hence the shift to the benzoxazole scaffolds. In the article, the most potent inhibitors of mpges-1 were compounds designated by numbers 2 and 3. No efficacy and selectivity were reported in these compounds and were therefore abandoned. A prior study with a benzoxazole (designated by a number 5) done by High Throughput Screening (HTS) revealed modest enzyme assay activity but didn’t have potency the cell-based assay. Five had, at the fifth position, a chlorine atom and any attempts to replace it with methyl or hydrogen were futile and led to inactive analogs.

Other attempts with other electron withdrawing groups such as trifluoromethyl making compound 17 and bromo (13) offered no significant benefit compared to the chloro analog designated as 12. When the chloro substituent was replaced with smaller, polar substitutes, for example, cyano forming compound 14, ethanesulfonyl-forming compound 15 or formation of compound 16 by substituting with carboxamide caused a right-shift in the mpges-1 inhibitory activity. Generally, experiments with the benzoxazole analogs were done by careful modification or substitution of the most active portion of the right hand of the first compound that was designated as five by High Throughput Screening. This led to the production of compound 12. Aryl and fluoroalkyl compounds were introduced at the C6 position on the benzoxazole ring. This led to compounds 23, 26 and 29 being discovered.

A myriad of other compounds were found by these modifications, tested via the guinea pig carrageenan stimulated air pouch as a model of inflammation. This model was chosen because up to date; there is no single mpges-1 inhibitor that has ever been published in literature as having activity on the rodent enzyme. Therefore, historical inflammatory models used in carrying out preclinical studies of NSAIDs and cyclooxygenase isoenzyme two inhibitors could not be utilized. They were also passed through studies with rats and finally their action determined in human fetal fibroblast cells. These compounds were designated by numbers as will be seen in the results section. Naproxen, a non-steroidal anti-inflammatory drug was used as the check drug or the reference drug to compare the enzyme activity and other features of the compounds such as efficacy, potency, and bioavailability.

Experimental Results and Developments of PF-4693627

The following table shows the results of the pharmacokinetic properties that were obtained with different sample compounds. A 1 mg per kilogram intravenous dose of each compound was injected in Sprague Dawley rats. Bioavailability of the compounds was also determined by administering a 1mg per kilogram per oral dose in the same species of rats. Results for compound 26 (PF-4693627) have been highlighted.

Table 1

 (table from Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), Table 3)

Prostaglandin E2 inhibition in the guinea pig carrageenan air pouch model for three compounds was also done and results were compared against Naproxen as shown in the table below.

Table 2

(table from Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), Table 4) 

Compound 26, more attractive to produce compared to others, was experimented with different enzymes to assess its selectivity against the respective enzymes and the results were as below.

Table 3

(table from Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), Table 5)

The reference article describes the processes that happened to lead to the discovery of PF-4693627, referred to as compound 26. Many compounds were derived from the benzoxazole ring and tests done before compound 26 was chosen to be pursued. At the time the publication was being made, the compound PF-4693627 was undergoing pre-clinical trials. The published work, therefore, represents the preclinical trial stage of the development of compound 26 (PF-4693627).

Drug development takes various stages before it is fully allowed into the market. According to the Food and Drug Administration (FDA) and Chien, J. Y., Friedrich, S., Heathman, M. A., de Alwis, D. P., & Sinha, V. (2005), there are five stages which include: Discovery and development, Preclinical research, clinical research, Drug review by the organization and lastly, Post-market drug safety monitoring by the organization. The first stage of PF-4693627 was done by a realization that benzoxazole analogs have the enzyme prostaglandin E2 synthase inhibitory properties. Later, development of different analogs from the benzoxazole ring gave a wide variety of compounds were discovered that were recruited to preclinical research. The details of the preclinical research and the methods used are presented in the publication. Before PF-4693627 could be tested in people, it had to undergo the preclinical research to find out any potential toxicities.

From the results presented above in table 1, the in vivo rat pharmacokinetic properties of PF-4693627, represented in the table by compound 26 reveals a very high bioavailability of the drug compared to other compounds and only beaten by compound 29 and 12. The compound has a discouraging short half-life of just 0.51 hours. Compound 26 is beaten by compound 29 regarding volume of distribution and half-life.

Pharmacokinetic Properties of PF-4693627 and Comparison with Other Compounds

However, in table 2, the Guinea Pig carrageenan stimulated air pouch model experiment reveals compound 29 as having the lowest plasma concentration compared to the compounds 23,26 and Naproxen, the comparative drug at the same dose of 10mg per kilogram. This leaves compound 23 as the only competitor to PF-4693627. Compound 23 has the highest inhibitory activity against prostaglandin E₂ synthase enzyme compared to the rest. However, compound 26 was chosen to proceed to clinical trials with the potential to become the next novel agent in the management of osteoarthritis and rheumatoid arthritis because of several reasons. The compound is highly selective, has high in vitro potency, good in vivo efficacy, excellent preclinical safety profile and excellent pharmacokinetic properties. It is also preferred to compound 23 and 29 because it is easier and therefore attractive to manufacture. If it goes through the next stage of clinical trials successfully, it may potentially become a relief for patients suffering from osteoarthritis and rheumatoid arthritis due to the cardiovascular and gastrointestinal side effects they experience from prolonged use of NSAIDs.

A lot of progress has been made in this area of microsomal prostaglandin E₂ synthase inhibitors. Luz, J. G., Antonysamy, S., Kuklish, S. L., Condon, B., Lee, M. R., Allison, D., … & Russell, M. (2015) describes mpges-1 inhibitor crystal structure complexes as a basis for the design of more potent anti-inflammatory and analgesic therapeutics. Research in this project has expanded further as the same enzyme inhibitors have been discovered to have anti-cancer activities.

To take this project to the next level, that is; to take the drug PF-4693627 to the stage of drug review by the drug administrative organizations such as the Food and drug administration, there are several things it must achieve in the clinical trials which are currently undergoing. In the experiments on patients, the safety, effectiveness, and efficacy of the drug must be established. These are the three test it must pass for it to be reviewed and post-marketing surveillance done. The success rate of clinical trials according to BIO, Amplion and BioMedTracker’s 2006-2015 data is put at about 25% to 30%. PF-4693627 will have to be among the 30% to proceed to the next level. Results from the clinical studies should, therefore, reveal PF-4693627’s greater safety compared to existing anti-inflammatory agents, have better efficacy and be more effective.

The results obtained during the preclinical studies should be reproduced in the clinical trials for PF-4693627 to have any chance of seeing the drug market.

The ability of PF-4693627 to address inflammatory disorders is unquestionable. If it passes the clinical trials, this will be the most selective anti-inflammatory agent the world has ever discovered, only having effects during inflammation and having no effects during the normal body conditions. The drug achieves this by inhibiting only the microsomal form of the prostaglandin E₂ synthase enzyme, whose substrate rises only under inflammatory conditions. It spares all the other prostaglandins and leukotrienes blocked by other agents such as corticosteroids and Non-Steroidal Anti-inflammatory agents. PF-4693627 is a perfect replacement for these agents and a dream come true for patients with incurable inflammatory disorders such as osteoarthritis. 

PF-4693627, a mpges-1 inhibitor is a potential substitute for current ant-inflammatory agents. Having effectively passed the preclinical trials with greater safety, potency, bioavailability, and efficacy, it’s expected that clinical trials will be successful. It already showed the best safety profiles. Safety is the most significant setback of the current anti-inflammatory drugs with a myriad of side effects ranging from cardiovascular disorders to peptic ulcers. This drug will be a relief for patients who need long-term ant-inflammatory agents such as patients with osteoarthritis. The drug may also turn out to be useful in the treatment of cancer pain and inflammation.  

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