Tyrosine and glycine derivatives as potential prodrugs: design, synthesis, and pharmacological evaluation of amide derivatives of mefenamic acid.
This study deals with the synthesis, pharmacological activity, and kinetic studies of mefenamic acid (MA) prodrugs of tyrosine and glycine. The synthesis involved a series of protection and deprotection reactions. The hydrolysis of these prodrugs in the intestine was confirmed by hydrolysis kinetics studies in simulated gastric fluid, simulated intestinal fluid, and 80% plasma. The prodrugs were also evaluated for analgesic, anti-inflammatory, and ulcerogenic activities. The glycine prodrug showed maximum analgesic activity of 86%, and both tyrosine and glycine prodrugs showed better anti-inflammatory activity of 74% and 81%, respectively, when compared to the 40% of MA. Further, the prodrugs showed fewer gastric ulcers compared to MA; tyrosine and glycine prodrugs had an average ulcer index of 9.1 and 4.5, respectively, while an average ulcer index of 24.2 was observed with MA. These findings suggest that both prodrugs are better in action as compared to MA, and are advantageous in having fewer gastrointestinal side effects.
Rasheed
Arun
A
Department of Pharmaceutical Chemistry, Sree Vidyanikethan College of Pharmacy, Sree Sainath Nagar, Tirupati, Andhra Pradesh, India. arunrasheed@rediffmail.com
Ashok Kumar
C K
CK
D000577:Amides / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005750:Gastric Juice / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D005998:Glycine / Q000031:analogs & derivatives*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D008528:Mefenamic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D010147:Pain Measurement; D011355:Prodrugs / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D012995:Solubility; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives*
D000577:Amides; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D008528:Mefenamic Acid; D014443:Tyrosine; D005998:Glycine