title: Combining anticholinergic and anti-inflammatory activities into a single moiety: a novel approach to reduce gastrointestinal toxicity of ibuprofen and ketoprofen.
abstract: With the aim of reducing the local gastric irritation associated with non-steroidal anti-inflammatory drugs, a series of N,N-disubstituted aminoalcohol ester derivatives of ibuprofen and ketoprofen were synthesized and evaluated. The esters were specially designed to possess the anticholinergic activity in the intact form and exhibit the anti-inflammatory action after hydrolysis to the respective parent drug. The rationale being that besides blocking the acidic carboxylic group of the parent drug, the existence of the anticholinergic effect in the intact molecule would further aid in reducing the gastrointestinal mucosal damage by decreasing the gastric secretions and motility. All the ester derivatives were found to be stable in acidic and basic buffers. The synthesized derivatives, with experimentally proven good anti-inflammatory and anticholinergic activities, showed significant reduction of ulcerogenicity in the stomach. These results are attributed to the acquired anticholinergic activity with a simultaneous reduction of acidic character compared to the parent compounds. The study offers a new strategy for design and development of compounds with safer therapeutic profile for long-term treatment of inflammation-associated disorders.
authors.affiliation: Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, The M.S. University of Baroda, Vadodara, Gujarat, India.
authors.forename: Parmeshwari K
authors.initials: PK
authors.lastname: Halen
authors.forename: Kewal K
authors.initials: KK
authors.lastname: Chagti
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.forename: Mange R
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000633:toxicity; D018680:Cholinergic Antagonists / Q000737:chemistry / Q000633:toxicity; D015195:Drug Design; D004952:Esters; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry* / Q000633:toxicity*; D007660:Ketoprofen / Q000737:chemistry* / Q000633:toxicity*; D008297:Male; D023421:Models, Animal; D010437:Peptic Ulcer / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018680:Cholinergic Antagonists; D004952:Esters; D007660:Ketoprofen; D007052:Ibuprofen