title: Propyphenazone-based analogues as prodrugs and selective cyclooxygenase-2 inhibitors.
abstract: Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University , 61519 Minia, Egypt ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University , Jeddah 21589, Kingdome of Saudi Arabia.
authors.forename: Mohamed F
authors.initials: MF
authors.lastname: Radwan
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University , 61519 Minia, Egypt ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University , Jeddah 21589, Kingdome of Saudi Arabia ; Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Tamer S
authors.initials: TS
authors.lastname: Kaoud
keywords: NSAIDs; Prodrugs; cyclooxygenase-2 selective; drug design; propyphenazone