Synthesis and Evaluation of 6-Nitro-7-(1-piperazino)quinazolines: Dual-Acting Compounds with Inhibitory Activities toward Both Tumor Necrosis Factor-α (TNF-α) Production and T Cell Proliferation

Masanori Tobe; Yoshiaki Isobe; Hideyuki Tomizawa; Takahiro Nagasaki; Masamitsu Aoki; Toru Negishi; Hideya Hayashi

doi:10.1248/cpb.51.1109

Notes

Synthesis and Evaluation of 6-Nitro-7-(1-piperazino)quinazolines: Dual-Acting Compounds with Inhibitory Activities toward Both Tumor Necrosis Factor-α (TNF-α) Production and T Cell Proliferation

Masanori Tobe, Yoshiaki Isobe, Hideyuki Tomizawa, Takahiro Nagasaki, Masamitsu Aoki, Toru Negishi, Hideya Hayashi

著者情報

キーワード: tumor necrosis factor-α production, T cell proliferation, 6-nitroquinazoline, lipophilicity

ジャーナルフリー

2003 年 51 巻 9 号 p. 1109-1112

DOI https://doi.org/10.1248/cpb.51.1109

詳細

抄録

We investigated the chemical modifications of the nitroquinazoline derivative (1) through the replacement of the NH group at the C(4)-position with several N-alkyl groups to increase the lipophilicity at the C(4)-position. Among them, we found that the N-methyl analogue (5a) showed a 2-fold loss in the inhibitory activity toward tumor necrosis factor-α (TNF-α) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-α production with an ED₅₀ value of 26 mg/kg, whereas 1 did not. Moreover, the oral bioavailability of 5a was higher than that of 1 (1, F=1%; 5a, F=21%), and the calculated ClogP value for 5a was higher than that for 1. These results suggest that the improved lipophilicity of 5a compared with that of 1 reflects its greater inhibitory activity on TNF-α production in vivo as well as oral bioavailability.

責任著者(Corresponding author)

J-STAGEへの登録はこちら（無料）