Synthesis, characterization, and biological evaluation of novel diclofenac prodrugs.
Diclofenac ester pro drugs (4, 5, 6) were synthesized and evaluated in vitro and in vivo for their potential use for oral delivery, with the aim of obtaining enzymatically labile and less ulceration drugs than the parent drug diclofenac sodium (1a). Prodrugs 4, 5, 6 were found to be potent anti-inflammatory drugs with less ulcerogenic potential than the parent diclofenac sodium. Prodrugs 4, 5, 6 rapidly underwent enzymatic hydrolysis to release the parent drug diclofenac in 30-60 min in rat liver microsomes (RLM) and rat plasma (RP). Prodrugs were found to be more lipophilic when the partition coefficient was measured in 1-octanol and buffer system at pH 7.4 and 3.0. Diclofenac prodrugs 4, 5, 6 were found to be crystalline in nature (analyzed by PXRD). Prodrug 4 was found to be a superior candidate for the treatment of chronic inflammatory diseases.
Medicinal Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur 413 255, India. bandgar_bp@yahoo.com
Babasaheb P
BP
Bandgar
Rajendra Janardan
RJ
Sarangdhar
Fakrudeen Ali
FA
Ahamed
Santosh
S
Viswakarma
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D001711:Biotransformation; D002351:Carrageenan; D018360:Crystallography, X-Ray; D004008:Diclofenac / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004355:Drug Stability; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004952:Esters; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010949:Plasma; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D011355:Prodrugs; C558510:pivoloxymethyl 2-((2,6-dichlorophenyl)amino)benzeneacetate; D004008:Diclofenac; D002351:Carrageenan