Synthesis, in vitro skin permeation studies, and PLS-analysis of new naproxen derivatives.
OBJECTIVE
To synthesize new naproxen (01) derivatives with amide or ester structures or with a combination of the two (02-15). To compare their physicochemical properties with naproxen esters (16-22) and their respective skin permeation behavior. To study structure-permeation relationships via partial least squares (PLS)-analysis.


METHODS
Stability, aqueous, and octanol solubility were determined. Lipophilicity and further 53 chemical descriptors were computed. A suitable in-vitro skin permeation model was developed to compare maximal flux (Jmax) of derivatives. Based on these flux data, PLS-analysis was performed to derive structure-permeation relationships.


RESULTS
None of the new derivatives showed an improved flux in comparison to naproxen. This result can be explained by PLS-analysis: skin permeation increases with the solubility both in water and in octanol. For a good permeation, an optimized molecule should exhibit a small volume with a spherical shape. The surface area should be large in relation to volume, as indicated by the rugosity parameter. A clear separation between the hydrophobic and the hydrophilic domain (= high amphiphilic moment) is favorable. Lipophilicity is inversely correlated with skin permeation.


CONCLUSIONS
PLS-analysis is a valuable tool to derive significant, internally predictive quantitative models for structure-permeation relationships of naproxen derivatives in the above described skin permeation assay.
Weber
H
H
Department of Pharmaceutical Chemistry, Heinrich-Heine-Universität Düsseldorf, Germany. Horst.Weber@uniduesseldorf.de
Steimer
U
U
Mannhold
R
R
Cruciani
G
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002855:Chromatography, Thin Layer; D004058:Diffusion; D005260:Female; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D009288:Naproxen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D012869:Skin Absorption; D012995:Solubility; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007202:Indicators and Reagents; D009288:Naproxen