Design and synthesis of inhibitors of inducible nitric oxide synthase. Discovery of a new chemical lead with potential for oral bioavailability.
A series of 2-iminopiperidines fused to small-membered rings (Tables 1 and 2) were synthesised and biologically evaluated using an in vitro human nitric oxide synthase (NOS) inhibition assay. Fused bicyclic compounds 5-9 exhibited nearly the same potency as compound 1 in the hiNOS inhibition assay. Among these, the 1-methyl analogues 8 and 9 showed better isoform selectivity than their corresponding unsubstituted analogues 7 and 6, respectively. Compounds 5 and 6 were also evaluated by an in vivo NO accumulation assay in a mouse model. The discovery process of new chemical leads for an orally bioavailable inhibitor of human inducible NOS (iNOS) is reported. The structure-activity relationship (SAR) study and chemistry of these compounds are also reported.
Kawanaka
Yasufumi
Y
Fukui Research Institute, Ono Pharmaceutical Co. Ltd., Technoport, Yamagishi, Mikuni, Fukui 913-8538, Sakai, Japan. kawanaka@ono.co.jp
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
Nakai
Hisao
H
Toda
Masaaki
M
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; 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