Synthesis and in Vitro Evaluation of Novel Morpholinyl- and Methylpiperazinylacyloxyalkyl Prodrugs of 2-(6-Methoxy-2-naphthyl)propionic Acid (Naproxen) for Topical Drug Delivery

Citations Over TimeTop 10% of 2000 papers

Abstract

Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c-f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a-f were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the morpholinyl- or (4-methyl-1-piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP) and quantitatively hydrolyzed (t(1/2) = 1-26 min) to naproxen in human serum. Compounds 3c-f showed higher aqueous solubility and similar lipophilicity, determined by their octanol-buffer partition coefficients (log P(app)), at pH 5.0 when compared to naproxen. At pH 7.4 they were significantly more lipophilic than naproxen. The best prodrug 3c led to a 4- and 1.5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperazinyl group yields prodrugs that are partially un-ionized under neutral and slightly acidic conditions, and thus, a desirable combination is achieved in terms of aqueous solubility and lipophilicity. Moreover, the resulting combination of biphasic solubility and fast enzymatic hydrolysis of the methylpiperazinylacyloxyalkyl derivatives gave improved topical delivery of naproxen.

Related Papers

• → Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution(2003)361 cited
• → Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes(2018)36 cited
• → Potential prodrugs of non-steroidal anti-inflammatory agents for targeted drug delivery to the CNS(2004)46 cited
• → Lipophilicity of BODIPY fluorophores and their distribution in 1-octanol–water system(2023)2 cited
• → Synthesis, Characterization and Pharmacological Evaluation of Ester Prodrugs of Naproxen(2011)