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Non-Steroidal Anti-Inflammatory Drugs

Nikita Shokur

25 April 2014

Medicinal Chemistry
Introduction:

Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs from diverse structural

classes that show analgesic, anti-inflammatory, and antipyretic activities. Ever since the

development of NSAIDs, the need for these drugs has been exponentially growing due to the

broad range of applications for these medications and the recent development of selective COX-

2 inhibitors. The use of NSAIDs is seen primarily in patients with musculoskeletal illnesses.

Their use relieves temporary conditions such as sprains, strains, back pain, headaches, menstrual

cycle pains, colon polyps and long term conditions such as rheumatoid arthritis, osteoarthritis,

ankylosing spondylitis, lupus, and clotting of blood.1 However, NSAIDs have also shown

extensive adverse effects including gastrointestinal bleeding, peptic ulcer disease, hypertension,

edema, and renal disease.2 In 2012, the use of NSAIDs has been associated with the risk of acute

myocardial infarction.3

NSAIDs act by blocking cyclooxygenase enzyme systems. In 1990, an important

discovery was made differentiating between the two forms of cyclooxygenase enzyme: the COX-

1 that produces prostaglandins and thromboxanes that regulate gastrointestinal, renal, and

vascular functions and COX-2 that regulates the produces prostaglandins involved inflammation,

pain, and fever.4 In the past two decades, an enormous commercial development of selective

COX-2 enzyme inhibitors, known as coxibs, has been started. The idea was to reduce the

stomach bleeding caused by the inhibition of COX-1 enzyme, which protected the stomach

lining with mucous otherwise destroyed by acid.

Today, the use of NSAIDs continues to grow at an incredible rate. Between 1984 and

1988, the number of patients receiving prescriptions for NSAIDs jumped from 44 million to 70

million; by 1997 the worldwide market for these medications was over six billion dollars.2
Recent development of COX-2 selective inhibitor Celebrex has brought in four billion dollars

since its debut in 1999 and became the sixth best-selling drug.5 Other classes of NSAIDs include

Fenamates, Indole Acetic Acids, Oxicams, Propionic Acids, and Salicylates (Figure 1).6

Figure 1. Major Classes of NSAIDs.


Discovery:

The first signs of NSAIDs use dates back about 3500 years when Greek physician

Hippocrates prescribed willow bark and leaves to reduce fever and inflammation.7 In the 17th

century, salicin was identified as an active component of willow bark; in the midst of the

following century, Germany started producing salicylic acid. It wasnt until the 1899 that

salicylic acid was converted to acetylsalicylic acid, a more palatable form currently known as

Aspirin, and marketed by Bayer (Figure 2).7

Figure 2. Acetylation of salicylic acid to acetylsalicylic acid.

Pharmocology:

The pharmacology of salicylates will be described. Other classes of drugs have similar

pharmacological properties and follow a comparably similar absorption, distribution,

metabolism, and excretion (ADME).

Salicylates act as antipyretic, analgesic, anti-inflammatory, and uricosuric drugs. The

inhibit blood clotting, which contributes to the prevention of strokes and heart attacks, due to

inhibition of thromboxane A2. Salicylates are given orally and have around a 55%

bioavailability.2 Majority is absorbed in the small intestine and some are absorbed in the stomach

due to passive diffusion. Absorption takes between 20-30 minutes after oral intake as it is readily
hydrolyzed in blood and liver .8 They are distributed throughout most of the bodys tissues.

Salicylates are initially converted to salicylic acid. Average elimination time is about 24 hours;

inactivation occurs in the hepatic endoplasmic reticulum and mitochondria. Majority of it is

excreted after undergoing conjugation with glycine or with glucuronic acid to form ether or ester,

while around 10% of it is excreted as a free acid, and trace amounts salicylates are hydroxylated

before excretion.2,8

SAR:

General Structure Activity Relationship (SAR) for all anti-inflammatory non-steroidal

drug has been identified.8 All agents must possess a center of acidity represented by groups such

as carboxylic acids, enols, sulfanomide, or tetrazole groups. Amide or ester derivatives of

carboxylic acids are usually attributed to the metabolic hydrolysis products. The center of acidity

for NSAIDs is generally located a distance of one carbon away from a flat surface represented by

an aromatic or hetero-aromatic ring. This distance plays a critical role because as the distance

increases the activity of the drug diminishes. Aryl and hetero-aryl derivatives are common since

they correlate with the double bond at the 5- and 8- position of the arachidonic acid (Figure X).

Substitution of a methyl group on the alpha carbon has shown to increase anti-inflammatory

activity. The resulting derivatives, alpha-methyl acetic, have been given a class name profen.

Groups larger than methyl show a decline in activity. The importance of the methyl group comes

from a creation of a new chiral center; the anti-inflammatory activity is associated with the S (+)

enantiomer. The activity is further enhanced by an addition of a second area of lipophilicity that

is non-coplanar with the original aromatic or hetero-aromatic ring. This second lipophilic area

corresponds to the double bond region at the positon 11- of arachidonic acid.
Figure X. Arachidonic Acid.

Mechanism of Action:

The discovery of the mechanism of aspirin by John Vane in the seventies has spiked our

ability to develop NSAIDs. In the early 90s, Needleman, Simmons, and Herschmans group

reported a presence of an isoform of cyclooxygenase, later named COX-2.7 While traditional

NSAIDs inhibited both COX-1 and COX-2, the adverse effects of gastrointestinal toxicity were

attributed to gastro protective prostaglandins and prostocyclins produced via COX-1 pathway.

Since then scientists and pharmaceutical companies have shifted their focus on developing

selective COX-2 inhibitors. Their efforts led to the first selective COX-2 inhibitor celecoxib and

followed by rofexocib (Figure X).


Figure X. COX-2 with bound Celecoxib.

Arachidonic acid is produced from fatty acids by Phosopholipadase A. Cyclooxygenase

then catalyzes the oxidation of arachidonic acid to prostoglandin G2, which is then reduced to

prostoglandin H2 (Figure X).7 COX-1 is compromised of 602 amino acids whereas COX-2 has

604 amino acids. The two isoforms share 60-65% homology.7 The major difference is the

substitution of Isoleucine-523 in COX-1 for Valine-523 in COX-2.9 This opens a new pocket for

binding and allows for selectivity.

There are two types of inhibition of cyclooxygenase: the irreversible ihibition and

competitive inhibition of the substrate. The irreversible inhibition is unique to Aspirin, the drug

permanently acetylates the key Serine-530 within the active site.8 This inhibition is irreversible

since plateles do not carry out protein synthesis, thus inhibition lasts the cells lifetime. The
competitive inhibition of the substrate (arachidonic acid) is reversible when the drug washes out

or is competing for the bidning site. The carboxylate part of the drug bonds to Arginine-120 and

Tyrosine-355.10 Methyl and the ring structures fit into the hydrophobic pocket.

Cyclooxygenase 1 enzymes are thought to be constitutive, being expressed in most of our

bodily tissues. While cyclooxygenase 2 enzymes is induced by cell-signaling proteins called

cytokines and is partially constitutive.Both are responsible for the physiological production of

prostaglandins. Prostaglandins have a wide range of functions.8 PGI2 and PGE2 are responsible

for pain by sensitizing nerve endings to bradykinin, histamine, and substance P. PGI2, PGD2, and

PGE2 are vasodilators responsible for inflammation. PGI2 protects the gastric mucosa. PGE2

maintains renal blood flow and is responsible for fever. TXA2 stimulates platelet aggregation.

PGD2 contracts uterus.

Figure X. Biosynthesis of prostaglandin from arachidonic acid via COX isoform pathway.
NSAIDs can be classified into four groups.7 Group 1 includes NSAIDs that

inhibit both COX-1 and COX-2 with very little selectivity. Group 2 includes NSAIDs that

inhibit COX-2 with 5-50 fold selectivity. Group 3 includes NSAIDs that inhibit COX-2 with

over 50 fold selectivity. And Group 4 shows weak inhibition of both cyclooxygenase isoforms.

Figure X. Classification of NSAIDs according to their COX-1/2 activities.

Future Developments:

Despite the promise of therapeutic effectiveness of the selective COX-2 inhibitors, there

have been cases reporting the arousal of severe cardiovascular effects with the use of these

inhibitors.8 Long-term clinical trials of rofecoxib, a Group 3 coxib, that indicated an increased

risk of myocardial infarction. A later analysis of a vast population has shown that the risk of

heart problems grew many folds while on rofecoxib compared to some older NSAIDs. These
effects may be related to the degree of selectivity of COX-1 and COX-2 inhibitors. COX-1

mediates the production of prostaglandins and thromboxanes, which are responsible for platelet

aggregation, and COX-2 produces prostacyclin, which regulates platelet aggregation. The

inhibition of only COX-2 significantly reduces the production of prostacyclins, whereas the

production of thrombaxanes is unaffected. Thus, future developments of NSAIDs may be aimed

at preferentially inhibiting COX-2 while also having an inhibition on COX-1 to a lesser extent.

Recent research has also shown a link between COX-2 and cancer. The study revealed an

over-expression of COX-2 mRNA in colorectal cancer.12 Levels of COX-2 mRNA were found

overexpressed in almost 80% of the colorectal tumors compared to normal colorectal mucosa.

This suggests that COX-2 could be used as a possible biomarker for the risk of cancer and that it

could be of value in chemoprevention of colon cancer.


References:

1. American College of Rheumatology Members. NSAIDs: Nonsteroidal Anti-inflammatory

Drugs American College of Rheumatology, 2012, Web.

2. Saraf, S. Non-Steroidal Anti-Inflammatory Drugs, PharmaMed Press, 2008, 12-13,

168-169.

3. Krotz, F.; Schiele, T. M.; Klauss, V.; Sohn, H. Y.; Selective COX-2 inhibitors and risk of

myocardial infarction Journal of Vascular Research, 2005, 42(4), 312-24.

4. Rainsford, K. D. Anti-Inflammatory Drugs In the 21st century Subcellular Biochemistry,

2007, 42, 3-27.

5. Halpern, G.M. COX-2 Inhibitors: a story of greed, deception, and death

Inflammopharmacology, 2005, 13(4), 419-25.

6. Monteleone, G. Classes of NSAIDs SportsMedicine. Web.

7. Pravee Rao, P.N.; Knaus, E.E. Evolution of Nonsteroidal Anti-Inflammatory Drugs

NSAIDs):Cyclooxygenase (COX) Inhibition and Beyond Journal of Pharmaceutical

Sciences, 2008, 11(2), 81-110.

8. Bkhaitan, M. Non-Steroidal Anti-inflammatory Drugs Department of Pharmaceutical

Chemistry, Web.

9. Gierse, J., McDonald, J., Hauser, S.; A Single Amino Acid Difference between

Cyclooxygenase-1 (COX-1) and 2 (COX-2) Reverses the Selectivity of COX-2 Specific


Inhibitors Journal of Biological Chemistry, 1996, 271, 15810-15814.

10. Dunlap, N. Enzyme Inhibitors Medicinal Chemistry, Custom Publishing, 2013, 88-93.

11. Billones, J.; Buenaobra, S. Quantitative Structure-Activity Relationship (QSAR)Study of

Cyclooxygenase-2 (COX-2) Inhibitors Philippine Journal of Science, 2008, 140(2),

125-132.

12. Roelofs, H. Over-expression of COX-2 mRNA in colorectal cancer Biomedical Central

Gastroenterology, 2014, 14(1).