Etoricoxib Database Entry DaMocles Group V: Steffen Haller, Rene Häußler, Jonas Kaffenberger, Julian Kirsch 1
Table of contents 1. General information... 3 2. Value of coxibs... 4 3. Structure... 5 4. Mechanism of action... 6 5. Disadvantages and adverse effects... 7 6. Possible way of synthesis... 8 7. List of sources... 10 8. List of figures... 10 2
1. General information Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) and thus, a pain reliever. Like coxibs in general, its pain relieving effect is based on selective inhibition of Cyclooxygenase 2 (COX-2), which is responsible for production of pain and inflammatory mediating type-2-prostaglandines. In Germany, the registered trade name for Etoricoxib is Arcoxia. It is available in dosages of 60, 90, and 120 mg. Etoricoxib is applied in case of rheumatism diseases like arthrosis, arthritis, gout, morbus bechterew. Additionally, it is used to treat toothache after tooth surgeries. A feature of Etoricoxib is its long half-life (22 hours). Therefore, only one daily intake of the drug is necessary. 3
2. Value of coxibs Cyclooxygenases are responsible for the production of prostaglandins from arachidonic acid. There are different forms of cyclooxygenases, and each form produces a special type of prostaglandin. Cyclooxygenase 1 (COX-1) produces type-1-prostaglandins, which are responsible for protection of the gastric mucosa and for hemostasis. However, the type-2-prostaglandins produced by cyclooxygenase 2 mediate pain, inflammation, and fever. The different types of prostaglandins appear to cause contrary effects. Usually, NSAIDs like acetylsalicylic acid are COX-1 and COX-2 inhibitors. However, the lack of type-1- prostaglandins caused by COX-1 inhibition causes side effects like malfunction of hemostasis and insufficient blood supply of the gastric mucosa. Selective COX-2-inhibitors like coxibs drastically reduce these side effects since they do not affect COX-1. Figure 1: Scheme of prostaglandin synthesis and its effects. 4
3. Structure Commonly, coxibs appear to have the following scaffold: Figure 2: Generic structure of coxibs. The rest R 1 may be a methyl group or simply a hydrogen atom. R 2 can be replaced by either a methyl group, a monosubstituted or an unsubstituted amine group. X depicts a (often substituted) heterocyclic aromatic rest. Figure 3: Structure of Etoricoxib. While the rests determine the drug s selectivities in action, the characteristic V-shape of coxibs is crucial for their use as COX-2-selective inhibitors: Their bulky appearance makes it impossible for the molekules to enter the active site of COX-1, whereas they are not too big to enter the active site of COX-2. 5
4. Mechanism of action In comparison to COX-1, some amino acids in the active site of COX-2 are replaced with amino acids with smaller side chains. The smaller side chains result in less steric hindrance for molecules to enter and bind to the active site. Hence, coxibs that are generally too bulky to enter the active site of COX-1 can bind to the active site of COX-2 instead. The oxygen atoms of the methylsulfone or sulfonamide group are responsible for the actual binding of the molecule, since the hydrogen atoms in side chains of the polar amino acids inside the active site (such as glutamine, arginine and histidine) form hydrogen bonds to these oxygen atoms. The different strenghts of binding and the differences in selectivity of coxibs are caused by electrostatical interactions between the specific phenyl or the heterocyclic scaffold and the side chains of non-polar amino acids within the active site. Figure 4: Binding and positioning of a Coxib at the COX-2 active site (Celecoxib is depicted). 6
5. Disadvantages and adverse effects Beside its antiphlogistic, analgetic and antipyretic effect, Etoricoxib also brings disadvantages. Amongst others, the disadvantages of Etoricoxib are an impairment of the kidney function and an increasement of preload for oedemata and hypertension. Furthermore, Etoricoxib causes a cardiovascular risk by missing inhibition of the aggregation of thrombocytes. This is caused by the selective blockade of cyclooxygenase 2. Therefore, more arachidonic acid is available for cyclooxygenase 1, whereby more prostagladine, for example thromboxan A2, is built, which causes blood clotting in the circulatory. Moreover, the risk of a coronary increases if Etoricoxib is ingested in a high dosis. The most appearing adverse effects of Etoricoxib are indigestion, sickness, tiredness, sensible heartbeats, vertigo, headaches and oedemata. Rarely Etorycoxib causes severe adverse effects like gastric and intestinal ulcer, cardiac desease and kidney diesease. 7
6. Possible way of synthesis This two step synthesis is taken from the patent EP2802564 B1 and is one of many different ways of synthesizing Etoricoxib. Figure 5: Possible way for synthesis of Etoricoxib. 5-Chloro-3-(4-methylthiophenyl)-6 -methyl-[2,3 ]bipyridine (4) by condensation of methylthiobenzylpyridylketone (3) with 2-chloromalonaldehyde (5) in acidic condition: Methylthiobenzylpyridylketone (3) (20g, 0.078mol) and 2-chloromalonaldehyde (5) (24.5g, 0.23mol) were added to a solution of propionic acid (140mL) and ammonium acetate (53.9g, 0.7mol). The mixture was heated to 130 C, and stirred for 16 hours. The amount of acid was reduced by distillation under reduced pressure. The remaining mixture was basified with 100mL NaCO3 solution (20%). The solution was extracted with ethyl acetate (70mL) 3 times. The combined organic solutions were treated with charcoal, filtered and dried with sodium sulfate. The solution was then filtered and evaporated under reduced pressure. The 5-chloro-3-(4-methylthiophenyl)-6 -methyl-[2,3 ]bipyridine (4) was obtained. Further purification of the solid was made by recrystallization involving dissolution of the solid in cyclohexane under heating above 40 C up to refluxing, charcoal treatment of the solution, removal of the charcoal by filtration, evaporation part of the solvent under reduced pressure, cooling of the remaining solution to 0-15 C, filtration and washing of precipitate with small amounts 8
of cyclohexane, drying in vacuum to give an off-white solid of the compound of formula (4) (17.3g, 68%), m.p. 108.0-109.5 C; Compound of formula (1) by oxidation of 5-Chloro-3-(4-methylthiophenyl)-6 -methyl-[2,3 ]bipyridine (4): To a solution of 5-chloro-3-(4-methylthiophenyl)-6 -methyl-[2,3 ]bipyridine (4) (50g, 0.15mol) and sulfuric acid (6g, 0.061mol) in methanol (300mL) was added sodium molybdate (1.2g, 0.004mol). The solution was heated to 55 C, and was added hydrogen peroxide (40mL, 30%). The reaction mixture was kept stirring for 15 min and NaHSO3 (60mL, 30%) was added. The reaction mixture then was cooled to room temperature, organic solvent was removed under reduced pressure and water (100mL) was added. The aqueous solution was washed with ethyl acetate (50mL) 2 times, treated with charcoal and filtered. The solution was basified by NaOH solution (20%) and the precipitate was collected, washed with water (50mL). The solid was recrystallized with aqueous ethanol solution and dried in vacuum to give an off-white solid (51.6g, 94%) of compound of formula (1), m.p. 135.5-135.9 C; 9
7. List of sources http://www.deutscher-apotheker-verlag.de/uploads/tx_crondavtitel/dateidatei/9783769263077_p.pdf, 20.06.2017. http://pdfaiw.uspto.gov/.aiw?pagenum=0&docid=20020016343&idkey=16bb6195be19&hom eurl=http%3a%2f%2fappft.uspto.gov%2fnetacgi%2fnph- Parser%3FSect1%3DPTO1%2526Sect2%3DHITOFF%2526d%3DPG01%2526p%3D1% 2526u%3D%25252Fnetahtml%25252FPTO%25252Fsrchnum.html%2526r%3D1%2526f%3DG%2 526l%3D50%2526s1%3D%25252220020016343%252522.PGNR.%2526OS%3DDN%2F2002001 6343%2526RS%3DDN%2F20020016343, 20.06.2017. http://www.medscape.org/viewarticle/473972_2, 20.06.2017. http://www.pharmawiki.ch/wiki/index.php?wiki=etoricoxib, 20.06.2017. https://en.wikipedia.org/wiki/discovery_and_development_of_cyclooxygenase_2_inhibitors, 21.06.2017. http://user.uni-frankfurt.de/~dingerma/podcast/nsar_aigen_2011.pdf, 21.06.2017. https://www.drugbank.ca/drugs/db01628, 21.06.2017. http://www.akdae.de/arzneimittelsicherheit/rhb/archiv/2005/65_20050200.pdf, 22.06.2017. https://de.wikipedia.org/wiki/etoricoxib, 27.06.2017. https://data.epo.org/publication-server/rest/v1.0/publicationdates/20160810/patents/ep2802564nwb1/document.pdf, 27.06.2017 8. List of figures http://img.medscapestatic.com/slide/migrated/editorial/cmecircle/2004/3065/images/weaver/fi gure007.gif, 21.06.2017. https://en.wikipedia.org/wiki/discovery_and_development_of_cyclooxygenase_2_inhibitors#/me dia/file:coxii-receptor.png, 21.06.2017. 10