抗アレルギー剤の開発におけるLead Evolution;　第二リード化合物としてのDimethyl(2-Phenoxyethyl) sulfonium <I>p</I>-Toluenesulfonate

Abstract

Derivatives of 2-hydroxyethyldimethylsulfonium p-toluenesulfonate (1) were evaluated for anti-allergic activity in order to develop the drug for treatment of type I allergic diseases. The IgE-induced rat homologous passive cutaneous anaphylaxis (PCA) was inhibited by some 2-alkoxy and 2-aryloxyethyl sulfonium p-toluenesulfonates. There were some correlations between hydrophobicity or electronic properties (HOMO or charge at the O atom) and anti-allergic activity or acute toxicity. Dimethyl(2-phenoxyethyl)sulfonium p-toluenesulfonate (5) was selected as a second lead compound in the next stage.

Optimal Lipophilicity of Sulfonium <i>p</i>-Toluenesulfonate as Anti-allergic Drug

“…On the other hand, the primary lead compound 20 showed the strong PCA inhibitory activity in ip administration (dose: 20 mg/kg, PCA inhibition: 72.7%), but the activity was remarkably attenuated in the oral (po) administration (dose: 50 mg, inhibition: 7.5%) ( Table 5). Then, the 2,3-dihydroxypropoxy moiety: -OCH 2 CH(OH)CH 2 OH was selected as an alkoxy group electron-donating moiety, and para (48), meta (49), and ortho (50) substituted derivatives were synthesized [7]. As a result, compared with the other positions, the para position produced better PCA inhibitory activity and toxicity (LD 50 ).…”

“…Therefore compound 52 having logK TLC of 0.07 was considered a good outlier with respect to activity and toxicity. Consequently, compound 52 was initially selected as a candidate for preclinical study [7]. Nevertheless, we considered that the cholinergic toxicity of this compound was not completely eliminated, and therefore we continued further to examine new lead compounds [8].…”

“…During the development of Suplatast Tosilate (IPD-1151T) (67) (Chart 1), which is a Th2 cytokine inhibitor and used as anti-allergic drug [3], we have reported some QSAR analysis by using only the calculated values as lipophilic parameter [5][6] [7][8] [9] [10], because the logK values of sulfonium compounds had been previously only rarely measured. We could comprehend the relative lipophilicity of sulfonium compounds in the developmental process (Chart1), but we did not determine a suitable logK value for the anti-allergic activity and toxicity.…”

Dimethyl(2-phenoxyethyl)sulfonium <I>p</I>-Toluenesulfonate の抗アレルギー剤開発におけるリード最適化

“…Antiserum containing homocytotropic antibody was obtained from rats that had been immunized with 2,4-dinitrophenyl-coupled ascaris (DNP-As) mixed with killed Bordetella pertussis according to the method of Tada et al [4] The antibody titer of this serum (rat anti-DNP-As serum ) was about 1:256 as estimated by a 48 h PCA. The antiserum diluted 20-fold with 0.9% saline was injected intradermally in 0.1 mL doses into 3 sites on the shaved backs of normal rats (The number of animals is 7 or 8).…”

“…We have found some kinds of sulfonium compounds that have immunological activity and have chosen 2-hydroxyethyldimethylsulfonium p-toluenesulfonate as a lead compound [3]. Furthermore, as a second lead compound, dimethyl(2-phenoxyethyl)sulfonium p-toluenesulfonate (1) was selected by the PCA test [4]. As the next stage, we have carried out lead optimization by analyzing quantitative structure-activity relationships (QSAR) taking account of cholinergic activity as one of the side effects of drugs containing dimethylsulfonium compounds.…”