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Gelain, Arianna,Barlocco, Daniela,Kwon, Byong-Mog,Jeong, Tae-Sook,Im, Kyung-Ran,Legnani, Laura,Toma, Lucio WILEY-VCH Verlag 2006 Archiv der Pharmazie Vol.339 No.12
<P>A series of novel Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors 8a–f was synthesized; the substances were characterized by the presence of a 2,5-dimethylpyrazin-3-yl moiety at one end and a 3-heptylamino-5-phenylpyridazine system at the other one, linked through linear alkyl spacers of different length. The new derivatives were designed based on the hypothesis that the 3-amino-5-phenylpyridazine moiety could mimic the aryl substituted urea, which was present in a number of ACAT inhibitors previously described. The choice of the 2,5-dimethylpyrazin-3-yl substituent was supported by a preliminary investigation, which indicated that this moiety is the most powerful in conferring ACAT inhibitory properties to the new series. The pharmacological results proved the idea to be sound. Finally, compounds 9a–c, lacking the phenylpyridazine moiety were prepared and tested to further strengthen our hypothesis.</P>
Meneghetti, Fiorella,Villa, Stefania,Masciocchi, Daniela,Barlocco, Daniela,Toma, Lucio,Han, Dong‐,Cho,Kwon, Byoung‐,Mog,Ogo, Naohisa,Asai, Akira,Legnani, Laura,Gelain, Arianna WILEY‐VCH Verlag 2015 EUROPEAN JOURNAL OF ORGANIC CHEMISTRY Vol.2015 No.22
<P><B>Abstract</B></P><P>Three new ureido‐pyridazinone derivatives, which are structurally related to the known STAT3 inhibitor <B>AVS‐0288</B>, were designed by taking into account the structure–activity relationships determined for several ureido‐oxadiazole derivatives previously studied by our group. Their synthesis was first attempted through suitable 5‐aminopyridazinone intermediates (<B>6a</B> and <B>6b</B>), which molecular structures were confirmed by means of X‐ray diffraction data on <B>6a</B>. Amine functionalization was unsuccessful, therefore, an alternative method was devised. Dual‐luciferase and AlphaScreen‐based assays were used to test their activity. The obtained data were rationalized on the basis of a modeling study, which focused our attention on the geometrical preferences of the ureido moiety. Computational results seem to indicate that both the 1,2,5‐oxadiazole ring and the extended <I>ZZ</I> arrangement are essential and probably act in a synergistic way to confer significant activity against STAT3.</P>