Estimation of the lipophilicity of purine-2,6-dione-based TRPA1 antagonists and PDE4/7 inhibitors with analgesic activity

[摘要] Lipophilicity is one of the principal QSAR parameters which influences among others the pharmacodynamics and pharmacokinetic properties of a drug candidates. In this paper, the lipophilicity of 14 amide derivatives of 1,3dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 channel antagonists and phosphodiesterase 4/7 inhibitors with analgesic activity were investigated, using reversed-phase thin-layer chromatography method. It was observed that the retention behavior of the analyzed compounds was dependent on their structural features i.e. an aliphatic linker length, a kind of substituent at 8 position of purine-2,6-dione scaffold as well as on a substitution in a phenyl group. The experimental parameters (RM0) were compared with computationally calculated partition coefficient values by Principal Component Analysis (PCA). To verify the influence of lipophilic parameter of the investigated compounds on their biological activity the KruskalWallis test was performed. The lowest lipophilicity was observed for the compounds with weak PDE4/7 inhibitory potency. The differences between the lipophilicity of potent inhibitors and inactive compounds were statistically significant. It was found that the presence of more lipophilic propoxy- or butoxy- substituents as well as the elongation of the aliphatic chain to propylene one between the purine-2,6-dione core and amide group were preferable for desired multifunctional activity.

[发布日期] 2021-10-01

[关键词] Lipophilicity;Chromatography;Principal Component Analysis;Multifunctional ligands;Purine-2;6-dione