title: Synthesis and pharmacological evaluation of some dual-acting amino-alcohol ester derivatives of flurbiprofen and 2-[1,1'-biphenyl-4-yl]acetic acid: a potential approach to reduce local gastrointestinal toxicity.
abstract: The search for safer non-steroidal anti-inflammatory drugs (NSAIDs) continues with the failure of anticipated 'ideal' anti-inflammatory agents, the coxibs, on long-term usage. Increased gastric motility and acidity due to the free carboxy group are involved in the etiology of gastric toxicity, common to conventional NSAIDs. Keeping this fact in mind, it was planned to modify some of the conventional NSAIDs to amino-alcohol ester derivatives, which satisfied the structural requirements for these compounds to possess anticholinergic activity in the intact form. Besides blocking the acidic carboxylic group, incorporation of anticholinergic acivity in these molecules was expected to reduce the gastric toxicity by decreasing gastric acid secretion and motility. Synthesis and pharmacological evaluation of six different N,N-disubstituted amino-ethyl ester derivatives, structurally resembling the amino-alcohol ester class of anticholinergic agents, each for [1,1'-biphenyl]-4-acetic acid (3) and flurbiprofen (10), have been reported as potential substitutes for these NSAIDs, with improved therapeutic profile. All the ester derivatives were found to have sufficient chemical stability in buffers (pH 2.0 and 7.4), ensuring them to be absorbed as intact moieties from the gastrointestinal tract. A significant reduction in ulcerogenic potency in comparison to the parent drugs with a slightly higher anti-inflammatory potency suggests that the majority of these candidates have an improved therapeutic profile over their parent drugs. Hence, a promising novel approach, different from the conventional prodrug concept, has been successfully worked out to overcome the local gastric toxicity, yielding therapeutically better compounds for long-term oral anti-inflammatory therapy.
authors.affiliation: Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, India.
authors.forename: Parmeshwari Kuldeep Kumar
authors.initials: PK
authors.lastname: Halen
authors.forename: Kewal Krishna
authors.initials: KK
authors.lastname: Chagti
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.forename: Mange Ram
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D019342:Acetic Acid / Q000737:chemistry*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004952:Esters / Q000737:chemistry*; D005260:Female; D005480:Flurbiprofen / Q000737:chemistry*; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007082:Ileum / Q000378:metabolism; D008297:Male; D010648:Phenylacetates / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D010648:Phenylacetates; C012776:biphenylylacetic acid; D005480:Flurbiprofen; D019342:Acetic Acid