Prodrugs of NSAIDs: A Review

Abstract

Intoroduction: Prodrug approach deals with chemical biotransformation or enzymatic conversion or involves inactive or less active bio-reversible derivatives of active drug molecules. They have to pass through enzymatic or chemical biotransformation before eliciting their pharmacological action.

Methods & materials: The two different pharmacophores combine to give synergistic activity or may help in targeting the active drug to its target. Prodrug super seeds the problems of prodrug designing, for example solubility enhancement, bioavailability enhancement, chemical stability improvement, presystemic metabolism, site specific delivery, toxicity masking, improving patient acceptance, or eradicating undesirable adverse effects.

Results: As an outcome the search for a prodrug or mutual prodrug with reduced toxicity has continued during recent years. This present review emphasizes the common help to revamp physiochemical, pharmaceutical and therapeutic effectiveness of drugs.

Conclusion: This gives the researcher a common platform where they can find prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation, ulcergenocity and bleeding).

Keywords: Enzymatic attack; Gastrointestinal toxicity; NSAIDs; Prodrug; Synergistic; Ulcergenocity.

Fig. (1)

Classification of prodrug.

Fig. (2)

Schematic representation of carrier-linked prodrug and mutual prodrug.

Fig. (3)

Cefpodoxime proxetil.

Fig. (4)

Naproxen-2-glyceride.

Fig. (5)

Sulfasalazine.

Fig. (6)

Estramustine.

Fig. (7)

Phenylbutazone.

Fig. (8)

Chloromphenicol Palmitate.

Fig. (9)

Ethylmercaptan.

Fig. (10)

Salsalate.

Fig. (11)

Prodrug of Phenytoin.

Fig. (12)

Chloromphenicaol Sodium Succinate.

Fig. (13)

Cortisol.

Fig. (14)

Pivampicillin.

Fig. (15)

Glycerol Ester of Naproxen.

Fig. (16)

Naproxen-propyphenazone mutual prodrugs.

Fig. (17)

Estramustin.

Fig. (18)

Testosterone cypionate.

Fig. (19)

Testosterone propionate.

Fig. (20)

Fluphenazine enanthate.

Fig. (21)

Fluphenazine deaconate.

Fig. (22)

Mutual prodrugs of aspirin and paracetamol.

Fig. (23)

Ibuprofen guiacol ester.

Fig. (24)

Acetylsalicylic acid and paracetamol prodrug.

Fig. (25)

Indomethacin ester prodrug.

Fig. (26a)

Nitroxybutylesters of flubiprofen.

Fig. (26b)

Nitroxybutylesters of ketoprofen.

Fig. (27)

Cyclic paracetamol acetylsalicylic acid ester prodrug.

Fig. (28)

Ester prodrugs of diclofenac.

Fig. (29)

Mutual prodrug of chloroxazone and acetaminophen.

Fig. (30)

Carbamate codrugs.

Fig. (31)

Ethyl esters of flurbiprofen with arginine, lysine and p-guanidine L- phenylananine.

Fig. (32a)

Hydroxyethyl esters of mefenamic acid.

Fig. (32b)

Hydroxyethyl esters of diclofenac.

Fig. (33)

N- Hydroxymetyl phthalimide esters.

Fig. (34)

Prodrug of paracetamol esters.

Fig. (35)

Conjugate of Flubiprofen with histamine.

Fig. (36)

Prodrug of indomethacin and meclofenamic acid.

Fig. (37)

Nitrosothiol esters of diclofenac.

Fig. (38)

Morpholinyl and piperazinylalkyl esters of naproxen.

Fig. (39a)

First isomeric aspirin derivatives of isosorbide-5-mononitrate.

Fig. (39b)

Second isomeric aspirin derivatives of isosorbide-5-mononitrate.

Fig. (40)

Aminocarbonyloxymethyl esters.

Fig. (41)

Glycosamide esters of diclofenac and mefenamic acid.

Fig. (42)

Glycolamide ester prodrugs.

Fig. (43a)

Ketoprofen prodrug.

Fig. (43b)

Naproxen prodrug.

Fig. (43c)

Diclofenac prodrug.

Fig. (44a)

Amides of meclofenamic acid.

Fig. (44b)

Amides of meclofenamic acid.

Fig. (45)

Mefenamic acid-guaiacol ester.

Fig. (46)

Naproxen-propyphenazone hybrid drug ester.

Fig. (47)

Glycolamide naproxen prodrugs.

Fig. (48)

Ketoprofenamides.

Fig. (49)

NSAIDs prodrugs.

Fig. (50)

Ibuprofen with paracetamol.

Fig. (51)

Ibuprofen with salicylamide.

Fig. (52)

Mutual prodrugs of 4-BPA.

Fig. (53)

NSAIDs with L-cysteine ethyl ester.

Fig. (54)

Ester derivatives of mefenamic acid.

Fig. (55)

N,N- disubstituted aminoethyl ester derivatives of diclofenac.

Fig. (56)

N- arylhydrazone derivatives of mefenamic acid.

Fig. (57)

N,N-disubstituted aminoethyl ester derivatives of aspirin and ketorolac.

Fig. (58)

N,N-disubstituted amino-ethyl ester derivatives.

Fig. (59)

l-proline, trans-4-hydroxy-l-proline or dl pipecolinic acid prodrugs.

Fig. (60)

Indomethacin-TEG (Triethylene Glycol) ester and amide prodrugs.

Fig. (61)

Morpholinoalkyl ester prodrugs of niflumic acid.

Fig. (62)

Indomethacin with paracetamol mutual prodrug.

Fig. (63)

Alkyl ester prodrugs.

Fig. (64)

N,N-disubstituted aminoethanol ester.

Fig. (65)

N,N-disubstituted aminoalcohol ester.

Fig. (66)

Mefenamic acid prodrug of beta-cyclodextrins.

Fig. (67)

Aminocarbonyloxymethyl esters of diclofenac and flufenamic acid.

Fig. (68)

Naproxen and 6-methoxy-2-napthylacetic acid with aminoalcohol ester.

Fig. (69)

Indomethacin amide-nitrate derivative.

Fig. (70)

Piperazinylalkyl ester prodrugs of ketorolac.

Fig. (71)

Polymeric prodrugs of ibuprofen, ketoprofen and naproxen.

Fig. (72)

Prodrugs of ketorolac by amidation.

Fig. (73)

Prodrugs of flubiprofen by amidation.

Fig. (74a)

Aspirin prodrug.

Fig. (74b)

Indomethacin prodrug.

Fig. (75)

NO-Aspirin prodrug.

Fig. (76)

NO-Diclofenac prodrug.

Fig. (77)

Ester prodrugs of flurbiprofen, ibuprofen and ketoprofen.

Fig. (78)

Amide prodrugs of flurbiprofen, ibuprofen and ketoprofen.

Fig. (79)

Chloroxazone ester prodrugs of some NSAIDs.

Fig. (80)

Diclofenac with different antioxidants.

Fig. (81a)

Methyl esters of amino acids like histidine.

Fig. (81b)

Methyl esters of amino acids like alanine.

Fig. (81c)

Methyl esters of amino acids like tyrosine.

Fig. (81d)

Methyl esters of amino acids like glycine.

Fig. (82)

Aceclofenac with methyl esters of amino acids like histidine and alanine.

Fig. (83)

N-(5-phenylthiazol-2-yl) amides.

Fig. (84)

Amide prodrugs of diclofenac.

Fig. (85)

Proline ester prodrug of acetaminophen.

Fig. (86)

Nitrate [3-nitrooxyphenyl acetylsalicylate.

Fig. (87)

N-diazeniumdiolate.

Fig. (88)

Mutual prodrug consisting of 4-biphenylacetic acid and quercetin tetramethyl ether.

Fig. (89)

Amides of ibuprofen.

Fig. (90)

Ibuprofen with various sulfa drugs.

Fig. (91)

1-Oxy-benzo[1,2,5]oxadiazol-5-ylmethyl [2-(2,6-dichloro-phenylamino)-phenyl]-acetate, a new diclofenac derivative.

Fig. (92)

Ester and amide derivatives of some NSAIDs.

Fig. (93)

A group of hybrid ester prodrugs.

Fig. (94)

Codrug of nicotinic acid and ibuprofen.

Fig. (95)

Pyrrole-derived nitrooxy esters.

Fig. (96)

NSIADs with gabapentin via ester bonds.

Fig. (97a)

Aminoethylesters of ketorolac.

Fig. (97b)

Aminobutyl esters of ketorolac.

Fig. (98a)

Mefenamic acid, glycine and organic nitrates.

Fig. (98b)

Mefenamic acid, glycine and organic nitrates.

Fig. (99a)

4-((4-substituted benzylidene)amino)phenyl 2-(4-isobutylphenyl) propanoate.

Fig. (99b)

4-((4-substituted benzylidene)amino)phenyl 2-((2,4-dimethylphenyl)amino)benzoate.

Fig. (100)

Ibuprofen with naturally occurring phenolic and alcoholic compounds.

Fig. (101)

Prodrugs of dexibuprofen.

Fig. (102)

Rhein-NSAIDs prodrugs.

Fig. (103)

Co-drug of diacerein with antioxidant thymol.

Fig. (104)

Nicotinic acid conjugates with NSAIDs.

Fig. (105)

Mutual amide prodrug of ketorolac with glucosamine.

Fig. (106)

Mutual prodrug of diclofenac and paracetamol.

Fig. (107)

Morpholine ester of diclofenac.

Fig. (108)

Medoxinil prodrug of ibuprofen.

Fig. (109)

Propylphenazone with acidic NSAIDs.

Fig. (110)

Amide based prodrugs.