Synthesis, pharmacological activity and hydrolytic behavior of ethylenediamine and benzathine conjugates of ibuprofen.
For reducing the gastrointestinal toxicity associated with ibuprofen, its carboxylic group was masked by synthesizing its amide conjugates with ethylenediamine and benzathine (4a, 4b, respectively) by carbodiimide assisted coupling method. In vitro hydrolysis of conjugates showed that they were stable in HCl buffer (pH 1.2) indicating that the prodrugs did not break in stomach and there was no release of ibuprofen at gastric pH, whereas in phosphate buffer (pH 7.4) they undergo significant hydrolysis and thus release ibuprofen in adequate amounts following first order kinetics. The ibuprofen conjugates 4a, 4b were retaining anti-inflammatory activity intact and exhibited better analgesic activity along with much reduced ulcerogenicity. These findings suggested that both the conjugates are better in action as compared to parent drug and are advantageous in having less gastrointestinal side effects. Compound 4b however showed better analgesic activity and longer action (t(1/2)) than 4a, and hence it could be considered as a better candidate for prodrug among the two.
Chatterjee
Nithar R
NR
Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pharmaceutical Chemistry, Pimpri, Pune 411018, Maharashtra, India. nitharc@rediffmail.com
Kulkarni
Amol A
AA
Ghulekar
Santosh P
SP
D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005029:Ethylenediamines / Q000737:chemistry*; D005260:Female; D006868:Hydrolysis; D007052:Ibuprofen / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000188:drug therapy
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005029:Ethylenediamines; C031234:ethylenediamine; D002351:Carrageenan; C010044:benzathine; D007052:Ibuprofen