title: Synthesis, characterization and pharmacological evaluation of amide prodrugs of ketorolac.
abstract: Ketorolac (KC) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of KC were synthesized by amidation with ethyl esters of amino acids, namely, glycine, l-phenylalanine, l-tryptophan, l-valine, l-isoleucine, l-alanine, l-leucine, l-glutamic acid, l-aspartic acid and beta-alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for biopharmaceutical studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, anti-inflammatory activities were obtained in all cases as compared to KC. Among synthesized prodrugs, viz. AR-11, AR-19 and AR-20 showed excellent pharmacological response and encouraging hydrolysis rate both in SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent showed enhanced partition coefficient but diminished dissolution and hydrolysis rates. Such prodrugs can be considered for sustained release purpose.
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Dr. H.S. Gour Vishwavidyalaya, Sagar (M.P.) 470 003, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Mishra
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Veerasamy
authors.forename: Prateek Kumar
authors.initials: PK
authors.lastname: Jain
authors.forename: Vinod Kumar
authors.initials: VK
authors.lastname: Dixit
authors.forename: Ram Kishor
authors.initials: RK
authors.lastname: Agrawal
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D006801:Humans; D020910:Ketorolac / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship; D014456:Ulcer / Q000139:chemically induced
chemical_list: D000577:Amides; D011355:Prodrugs; D020910:Ketorolac