title: Synthesis, characterization and pharmacological evaluation of certain enzymatically cleavable NSAIDs amide prodrugs.
abstract: The presence of free carboxylic acid group in majority of non-steroidal anti-inflammatory drug (NSAIDs) is responsible from GI irritation. Coupling of the appropriate NSAIDs (diclofenac, naproxen, dexibuprofen and meclofenamic acid) 1-4, respectively with the appropriate amino acid ester 5 using dicyclohexylcarbodiimide afforded prodrugs 6-13. The structures of the prodrugs were verified based on spectral data. Chemical hydrolysis studies performed in three different non enzymatic buffer solutions at pH 1.2, 5.5 and 7.4, as well as in 80% human plasma and 10% rat liver homogenate using HPLC indicate no conversion of prodrugs to their respective NSAID in the studied buffers, while they underwent a reasonable plasma and rat liver homogenate hydrolysis. Furthermore, ulcerogenicity of prodrugs 9 and 12 were studied and results revealed no gastro-ulcerogenic effects.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Omdurman Islamic University, P.O. Box 2587, Khartoum, Sudan. Electronic address: Tilochem@yahoo.com.
authors.forename: Tilal
authors.initials: T
authors.lastname: Elsaman
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Omar A A
authors.initials: OA
authors.lastname: Aldeeb
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Assiut University, Assiut 71526, Egypt.
authors.forename: Tarek
authors.initials: T
authors.lastname: Aboul-Fadl
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Omdurman Islamic University, P.O. Box 2587, Khartoum, Sudan.
authors.forename: Elnazeer I
authors.initials: EI
authors.lastname: Hamedelneil
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000378:metabolism*; D008297:Male; D010949:Plasma / Q000378:metabolism; D011355:Prodrugs / Q000009:adverse effects* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs
keywords: Amino acid ester; NSAIDs; Prodrugs; Ulcerogenicity