Design and Synthesis of Orally Bioavailable Inhibitors of Inducible Nitric Oxide Synthase. Identification of 2-Azabicyclo[4.1.0]heptan-3-imines
Yasufumi Kawanaka
1
,
Kaoru Kobayashi
2
,
Shinya KUSUDA
2
,
Tadashi TATSUMI
2
,
Masayuki Murota
2
,
Toshihiko NISHIYAMA
2
,
Katsuya Hisaichi
2
,
Atsuko Fujii
2
,
Keisuke Hirai
2
,
MASAO NAKA
2
,
Masaharu Komeno
1
,
Yshihiko Odagaki
2
,
Hisao Nakai
2
,
Masaaki Toda
2
1
Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, Fukui 913-8538, Japan.
|
2
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan
|
Publication type: Journal Article
Publication date: 2003-04-07
scimago Q2
wos Q1
SJR: 0.608
CiteScore: 6.7
Impact factor: 3.0
ISSN: 09680896, 14643391
PubMed ID:
12659759
Organic Chemistry
Drug Discovery
Biochemistry
Molecular Biology
Pharmaceutical Science
Clinical Biochemistry
Molecular Medicine
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.
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Total citations:
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Citations from 2025:
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Kawanaka Y. et al. Design and Synthesis of Orally Bioavailable Inhibitors of Inducible Nitric Oxide Synthase. Identification of 2-Azabicyclo[4.1.0]heptan-3-imines // Bioorganic and Medicinal Chemistry. 2003. Vol. 11. No. 8. pp. 1723-1743.
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Kawanaka Y., Kobayashi K., KUSUDA S., TATSUMI T., Murota M., NISHIYAMA T., Hisaichi K., Fujii A., Hirai K., NAKA M., Komeno M., Odagaki Y., Nakai H., Toda M. Design and Synthesis of Orally Bioavailable Inhibitors of Inducible Nitric Oxide Synthase. Identification of 2-Azabicyclo[4.1.0]heptan-3-imines // Bioorganic and Medicinal Chemistry. 2003. Vol. 11. No. 8. pp. 1723-1743.
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TY - JOUR
DO - 10.1016/s0968-0896(03)00034-8
UR - https://doi.org/10.1016/s0968-0896(03)00034-8
TI - Design and Synthesis of Orally Bioavailable Inhibitors of Inducible Nitric Oxide Synthase. Identification of 2-Azabicyclo[4.1.0]heptan-3-imines
T2 - Bioorganic and Medicinal Chemistry
AU - Kawanaka, Yasufumi
AU - Kobayashi, Kaoru
AU - KUSUDA, Shinya
AU - TATSUMI, Tadashi
AU - Murota, Masayuki
AU - NISHIYAMA, Toshihiko
AU - Hisaichi, Katsuya
AU - Fujii, Atsuko
AU - Hirai, Keisuke
AU - NAKA, MASAO
AU - Komeno, Masaharu
AU - Odagaki, Yshihiko
AU - Nakai, Hisao
AU - Toda, Masaaki
PY - 2003
DA - 2003/04/07
PB - Elsevier
SP - 1723-1743
IS - 8
VL - 11
PMID - 12659759
SN - 0968-0896
SN - 1464-3391
ER -
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@article{2003_Kawanaka,
author = {Yasufumi Kawanaka and Kaoru Kobayashi and Shinya KUSUDA and Tadashi TATSUMI and Masayuki Murota and Toshihiko NISHIYAMA and Katsuya Hisaichi and Atsuko Fujii and Keisuke Hirai and MASAO NAKA and Masaharu Komeno and Yshihiko Odagaki and Hisao Nakai and Masaaki Toda},
title = {Design and Synthesis of Orally Bioavailable Inhibitors of Inducible Nitric Oxide Synthase. Identification of 2-Azabicyclo[4.1.0]heptan-3-imines},
journal = {Bioorganic and Medicinal Chemistry},
year = {2003},
volume = {11},
publisher = {Elsevier},
month = {apr},
url = {https://doi.org/10.1016/s0968-0896(03)00034-8},
number = {8},
pages = {1723--1743},
doi = {10.1016/s0968-0896(03)00034-8}
}
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MLA
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Kawanaka, Yasufumi, et al. “Design and Synthesis of Orally Bioavailable Inhibitors of Inducible Nitric Oxide Synthase. Identification of 2-Azabicyclo[4.1.0]heptan-3-imines.” Bioorganic and Medicinal Chemistry, vol. 11, no. 8, Apr. 2003, pp. 1723-1743. https://doi.org/10.1016/s0968-0896(03)00034-8.