Author/Authors :
Yasufumi Kawanaka، نويسنده , , Kaoru Kobayashi، نويسنده , , Shinya Kusuda، نويسنده , , Tadashi Tatsumi، نويسنده , , Masayuki Murota، نويسنده , , Toshihiko Nishiyama، نويسنده , , Katsuya Hisaichi، نويسنده , , Atsuko Fujii، نويسنده , , Keisuke Hirai، نويسنده , , Masao Naka، نويسنده , , Masaharu Komeno، نويسنده , , Yshihiko Odagaki، نويسنده , , Hisao Nakai، نويسنده , , Masaaki Toda، نويسنده ,
Abstract :
Further chemical modification of 2-iminopiperidines fused to cyclopropane rings was performed. Optically active isomers 2 and 13 were synthesized and their biological activity was evaluated. Compound 2 exhibited greater potency and more isoform selectivity than enantiomer 13 in the iNOS inhibition assay. One of the gem-chlorines on the fused cyclopropane moiety of 2 was eliminated to produce 3, which showed reduced potency for iNOS inhibition, as well as 4 with an increased potency. The isoform selectivity of 4 was also much higher than that of 3. This was also true for the corresponding methyl derivatives 6–9. The structure–activity relationship (SAR) study and computer aided docking study of the most optimized structure 4 with human iNOS will also be reported.
