Document Detail

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.
MedLine Citation:
PMID:  17193237     Owner:  NLM     Status:  MEDLINE    
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.
Parmeshwari Kuldeep Kumar Halen; Kewal Krishna Chagti; Rajani Giridhar; Mange Ram Yadav
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemistry & biodiversity     Volume:  3     ISSN:  1612-1880     ISO Abbreviation:  Chem. Biodivers.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-12-28     Completed Date:  2007-02-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197449     Medline TA:  Chem Biodivers     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  1238-48     Citation Subset:  IM    
Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, India.
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MeSH Terms
Acetic Acid / chemistry*
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*,  pharmacology*
Chemistry, Pharmaceutical / methods
Esters / chemistry*
Flurbiprofen / chemistry*
Gastrointestinal Tract / drug effects*
Hydrogen-Ion Concentration
Ileum / metabolism
Phenylacetates / chemistry*
Rats, Sprague-Dawley
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Esters; 0/Phenylacetates; 5104-49-4/Flurbiprofen; 51317-25-0/biphenylylacetic acid; 64-19-7/Acetic Acid

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