Synthesis, biological evaluation and kinetic studies of glyceride prodrugs of biphenyl acetic acid

Abstract

Glyceride derivatives (3a and 3b) of biphenyl acetic acid have been synthesized to reduce the gastrointestinal toxicity associated with it and are tested for their ulcerogenicity, anti-inflammatory and analgesic activity and hydrolytic behaviour. The prodrugs have been prepared by reacting 1,2,3-trihydroxypropane-1,3-dipalmitate/stearate 1 with the acid chloride of biphenyl acetic acid. The prodrugs are significantly less irritating to the mucosa as indicated by scores of 0.75 and 0.82 by 3a and 3b compared to 2.3 of biphenyl acetic acid. The prodrugs show better anti-inflammatory and analgesic activity than the parent drug. The hydrolysis studies of prodrugs show that the prodrugs are resistant to hydrolysis at pH 3, 4, 5 than at pH 7.4. The peak plasma concentration (Cmax) 28.63 <img src='/image/spc_char/micro.gif' border=0> g/mL of biphenyl acetic acid is attained in 2 hr whereas in case of 3a and 3b treated animals Cmax 33.5 and 34.6 <img src='/image/spc_char/micro.gif' border=0> g/mL is attained in 3 hr respectively. All these studies indicate that the glyceride prodrugs of biphenyl acetic acid might be considered as potential biolabile prodrugs of biphenyl acetic acid.