title: Synthesis and evaluation of 6-nitro-7-(1-piperazino)quinazolines: dual-acting compounds with inhibitory activities toward both tumor necrosis factor-alpha (TNF-alpha) production and T cell proliferation.
abstract: 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-alpha (TNF-alpha) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-alpha 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-alpha production in vivo as well as oral bioavailability.
authors.affiliation: Research Division, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tobe
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tomizawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagasaki
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Aoki
authors.forename: Toru
authors.initials: T
authors.lastname: Negishi
authors.forename: Hideya
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003864:Depression, Chemical; D006801:Humans; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D007202:Indicators and Reagents; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha