Cox 2 inhibitors

COX-2 inhibitors are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of celecoxib, rofecoxib, and other members of this drug class.Coxibs are NSAIDs that are highly selective for the COX2 enzyme. Because the COX2 enzyme mediates prostaglandin production responsible for inflammation and pain, coxibs are analgesic and antiinflammatory, but they lack the side effects related to inhibiting the COX1 enzyme (e.g., bleeding and gastrointestinal irritation).

1. Presentation on COX-2 Inhibitors Presented By Sukanta Debnath M.Pharm 1st semester Presented to DR. Kuntal Manna Associate Professor, Dept of Pharmacy Tripura University 1 Advanced Medicinal Chemistry-I

2. CONTENTS:- Introduction Types of cox Mechanism of cox Active site of cox 2 Structure of cox 2 isoenzyme Non steroidal anti inflammatory drugs Side effects of NSAIDs 2 VII. Categories of NSAIDs IX. Selective COX 2 inhibitors X. MOA of coxib XI. SAR of Non selective COX 2 inhibitors XII. Non selective COX 2 inhibitors XIII. Classification of Non selective COX 2 inhibitors XIV. Mechanism by which COX 2 contributes to Cancer

3. INTRODUCTION Cyclooxygenase  ( COX ), officially known as  prostaglandin-endoperoxide synthase  ( PTGS ), is an  enzyme   that is responsible for formation of  prostanoids , including  thromboxane  and  prostaglandins  such as  prostacyclin , from  arachidonic acid . A member of the  animal-type heme peroxidase  family, it is also known as  prostaglandin G/H synthase COX-2 inhibitors  are a type of  nonsteroidal anti-inflammatory drug  (NSAID) that directly targets cyclooxygenase-2,  COX-2 , an  enzyme  responsible for  inflammation  and  pain . 3

4. Types Of Cyclooxygenase (Cox) The  enzymes  that produce prostaglandins are called  cyclooxygenas e  (COX). There are two types of COX enzymes,  COX-1  and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining. 4

5. Mechanism Of Action 5 Arachidonic Acid Cox 2 (inducible) Cytokines, growth factor, Selective Cox 2 Inhibitors Classical NSAIDs Macrophage, Endothelial Cells, Brain , Kidneys, Reproductive Tract PGs Diseases Target:- Arthritis, Inflammation, Epithelial Neoplasms

6. Active sites of Cox 2 The cyclooxygenase active site is created by a long hydrophobic channel that is the site of non-steroidal anti-inflammatory drug binding. Cyclooxygenase sites where arachidonic acid is converted into hydroperoxyl endoperoxide prostaglandin G2 (PGG2) Heme site with peroxidase activity is responsible for the conversion of PGG2 to PGH2. Which is then converted into prostanoids ( PGD2 , PGF2 α , PGE2, thromboxane A2, PGI2) by specific isomerase enzyme. 6

7. Structure of Cox 2 isoenzymes 7 It is likely that Tyr-385 is acting as  a hydrogen bond donor to position the acetyl group adjacent to the hydroxyl group of  Ser-530 and to increase the reactivity. However, it is also possible that Tyr-385 is acting as a nucleophile and forming a transient O-acetyl-Tyr-385 that transfers acetyl to Ser-530. Arg-120 is located near the mouth of the hydrophobic channel that forms the cyclooxygenase active site of prostaglandin endoperoxide H synthases (PGHS-1). G uanido group of Arg-120 forms an ionic bond with the carboxylate group of arachidonate and that this interaction is an important contributor to the overall strength of arachidonate binding to PGHS-1

8. Non Steroidal Anti Inflammatory Drugs NSAIDS produce anti-inflammatory, anti-pyretic and analgesic effects. Finding ways of reducing pain and inflammation are key roles of NSAIDS. The mechanism of these drugs is due to their binding ability to the active sites of COX , preventing the catalysis of Arachidonic acid to prostaglandins 8

9. Contd….. NSAIDs binds irreversibly to COX enzymes and inhibit their action i.e the conversion of Arachidonic acid to the prostaglandins. NSAIDs acetylates the actives site of cox enzyme which causes inhibition. Some examples of NSAIDs are:-Aspirin . Ibuprofen . Piroxicam etc . Aspirin irreversibly inactivates both COX 1 and COX 2 by acetylation of a specific Serine residues. 9

10. Side Effects of NSAIDs 10

11. Selective Drug Targeting of COX 2 Selective Drug targeting to Cox 2 becomes possible by focusing on Hydrophilic side pocket present in Cox 2. 11

12. Categories of NSAIDs 12

13. Selective COX 2 inhibitors (COXIBs) As COX 2 has role in inflammation and pyrexia. So it is desirous to inhibit COX-2. There are different types of drugs that are used to inhibit COX-2 enzyme. COX-2 inhibitors (COXIBs) are a special category of NSAIDs that target only COX-2 enzymes. 13

14. Chemical Structures of Coxibs 14 CH3 Celecoxib celebrex Rofecoxib Vioxx Valdecoxib Parecoxib

15. MOA of Celecoxib Celecoxib is a nonsteroidal ant-inflammatory drug that exhibits ant-inflammatory, analgesic, and antipyretic activities. The mechanism of action of Celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclongenase-2 (COX-2), and at therapeutic concentrations in humans, Celecoxib does not inhibit the cycooxygenase-1(COX-1) isoenzyme. In colon tumour models, Celecoxib reduced the incidence and multiplicity of tumours. 15 N-(trifluroacetyl)imidazole acetophenone 1,3 Di carbonyl adduct 1,5 diaryl pyrazole

16. SAR of Selective COX 2 inhibitors A para sulfamoyalphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition. At the 3-position of the pyrazole, a trifluoromethyl or difluoro methyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution. In addition, a 4-sulfamoylphenyl in position no-1 is known to be necessary for COX-2 inhibition. replacing either of these entities with a –SO2NHCH3 substituent reduce the COX-2 inhibitory activity. 16

17. Non Selective COX 2 inhibitors Non-selective NSAIDs are drugs that inhibit both types of the COX enzyme and thus are associated with an increased risk of gastric ulceration, presumed to be both through the reduction in gastric protection that is provided by prostaglandins, as well as direct irritation of the gastric lining. One of the problems with NSAIDs is that they block both types of the COX enzyme, so while inflammation and pain were reduced, so were some of the good effects of prostaglandins such as protection of the stomach lining. 17

18. Classification of Non Selective COX 2 inhibitors 18

19. References https://www.drugs.com/drug-class/cox-2-inhibitors.html https://en.wikipedia.org/wiki/COX -2_inhibitor Structural and Functional Basis of Cyclooxygenase Inhibition Anna L . Blobaum  and  Lawrence J . Marnett . https://www.researchgate.net/publication/11592340_COX-2_inhibitors_Are_they_nonsteroidal_anti-inflammatory_drugs_with_a_better_safety_profile 19

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