Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Identification of 2-azabicyclo[4.1.0]heptan-3-imines.
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.
Kawanaka
Yasufumi
Y
Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, Fukui 913-8538, Japan.
Kobayashi
Kaoru
K
Kusuda
Shinya
S
Tatsumi
Tadashi
T
Murota
Masayuki
M
Nishiyama
Toshihiko
T
Hisaichi
Katsuya
K
Fujii
Atsuko
A
Hirai
Keisuke
K
Naka
Masao
M
Komeno
Masaharu
M
Odagaki
Yshihiko
Y
Nakai
Hisao
H
Toda
Masaaki
M
D000818:Animals; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D019323:omega-N-Methylarginine / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D007097:Imines; D010880:Piperidines; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse