DiclofenacJinay Kishorkumar Nagori

T.Y.B.Tech Pharmaceutical Sciences and Technology11PHT1004

PRESENTATION LAYOUT

Introduction1)

2)

5)

3)

4)

6) References

History

Metabolism

Structures

Physiochemical Properties

INTRODUCTIONDrug: Diclofenac (The name "diclofenac" derives from its chemical name: 2-(2,6-dichloranilino) phenyl acetic acid)Class: NSAIDsOrigin: Diclofenac originated from Ciba-Geigy (now Novartis) in 1973.Chemical type: Phenyl acetic acid type of NSAIDMedical use: Anti-inflammatory, Analgesic and Anti-Pyretic but majorly used in treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.Trivia: One of the most widely used NSAID in the world; more potent and better tolerated than other NSAIDs; available in 120 different countries; ranks among top prescription drugs in USA.Brand names: Voltaren, Volini, Reactine, Seradic, Diclonac etc.

Fig: Diclofenac Fig: Diclofenac (in 3D)

HISTORY (Rational Approach)

Aim was to synthesize an NSAID of high activity and outstanding tolerability.Assessing the physiochemical and structural properties of NSAIDs of that time, parameters considered were:

1. Drug transport through biological membranes;2. Structure of the molecule, which governs its fit to the receptor;3. Electronic structure, which controls the specific interaction between the

drug and the receptor.Conclusion obtained from the above study was (common features of indomethacin, phenyl butazone and mefenamic acid):

1. Acidity constant between 4 and 5;2. Two aromatic rings twisted in relation to each other;3. Similar degree of lipophilicity i.e. partition co-efficient ~ 10 (at

physiological pH).A receptor site was postulated that could accommodate arachidonic acid in a conformation that rationalizes its stereospecific conversion into cyclic endoperoxides.

COX enzyme inhibition is MOA of many NSAIDs, primary objective was to design a molecule that could antagonize the COX enzymes.

Initial binding may centre on the carboxylate group to anchor the substrate, which is then folded onto the enzyme hydrophobic surface (B) to form a hydrophobic pocket (C). The hydrogen at C-13 is abstracted homolytically from the bottom side of the folded substrate. This is immediately followed by topside addition of molecular oxygen to form the 11-peroxy radical.

A carboxylate (anionic) group to anchor the substrate and hydrophobic moiety of correct spatial characteristics to bind to the enzyme hydrophobic surface were found necessary.

Thus, the Diclofenac structure would have a carboxylic acid group (phenylacetic acid), secondary amine, hydrophobic moiety (phenyl ring with 2 chlorine atoms at ortho position for maximal twisting of the phenyl ring).The figure shows angle of torsion (α) and the intramolecular hydrogen bond (δ) between carboxyl oxygen and amino hydrogen.

PHYSIOCHEMICAL PROPERTIESPolar Surface Area:

PSA = 49.33 Å2

Partition Co-efficient:

LogP = 4.26

Fig: Hydrogen bond Donor/Acceptor Fig: pKa

METABOLISMRapidly and completely (~100%) absorbed on oral administration.The free acid (pKa = 4.0) is highly bound to serum proteins (99.5%), primarily albumin.Only 50 to 60% of an oral dose is bioavailable because of extensive hepatic metabolism.The major metabolite via CYP3A4 is the 4′-hydroxy derivative and accounts for 20 to 30% of the dose excreted, whereas the 5-hydroxy, 3′-hydroxy, and 4′,5-dihydroxy metabolites via CYP2C9 account for 10 to 20% of the excreted dose.The remaining drug is excreted in the form of sulphate conjugates.Although the major metabolite is much less active than the parent compound, it may exhibit significant biological activity, because it accounts for 30 to 40% of all of the metabolic products.

STRUCTURESpKa = 4.8LogP = 4.08PSA = 49.33 Å2

Change in structure:Both chlorine atoms replaced by methyl groups

pKa = 4.8LogP = 3.83PSA = 66.49 Å2

Change in structure:Carboxylic acid group replaced by tetrazole group

pKa = 4.13LogP = 5.20PSA = 37.30 Å2

Change in structure:Secondary amine group replaced by a branched alkyl group (C2)

pKa = 5.60LogP = 4.92PSA = 58.29 Å2

Change in structure:Carboxylic acid group replaced by hydroxy oxazole group

pKa = 5.2LogP = 4.54PSA = 49.33 Å2

Change in structure:Dicholorophenyl ring replaced by t-butyl thiophene

REFERENCES The History of Diclofenac-The American Journal of Medicine Volume 80 (suppl 4B). Foye’s Principles of Medicinal Chemistry – 6th edition www.chemicalize.orgDiclofenac Toxicity to Hepatocytes: A Role for Drug Metabolism in Cell Toxicity - The Journal of Pharmacology and Experimental Therapeutics Elements of Pharmacology – Dr. R. K. Goyal Wikipedia – Diclofenac www.molinspiration.com

THANK YOU!