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ABSTRACT: Effects of retro-inverso (RI) modifications of HTLV-1 protease inhibitors containing a hydroxyethylamine isoster backbone were clarified. Construction of the isoster backbone was achieved by a stereoselective aldol reaction. Four diastereomers with different configurations at the isoster hydroxyl site and the scissile site substituent were synthesized. Inhibitory activities of the new inhibitors suggest that partially modified RI inhibitors would interact with HTLV-1 protease in the same manner as the parent hydroxyethylamine inhibitor.
Bioorganic & medicinal chemistry 02/2010; 18(7):2720-7. · 2.82 Impact Factor
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Atsushi Naganawa,
Toshiaki Matsui,
Tetsuji Saito,
Masaki Ima, Tadashi Tatsumi,
Shingo Yamamoto,
Masayuki Murota,
Hiroshi Yamamoto,
Takayuki Maruyama,
Shuichi Ohuchida,
Hisao Nakai,
Kigen Kondo,
Masaaki Toda
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ABSTRACT: 4-({2-[Isobutyl(phenylsulfonyl)amino]-5-(trifluoromethyl)phenoxy}methyl)benzoic acid (1) is a functional PGE2 antagonist selective for EP1 receptor subtype. Analogs of 1, in which the phenyl-sulfonyl moiety has been replaced with more hydrophilic heteroarylsulfonyl moieties, exhibited more optimized antagonist activity, while some of them showed in vivo antagonist activity. Structure-activity relationship (SAR) studies are also presented.
Bioorganic & Medicinal Chemistry 11/2006; 14(19):6628-39. · 2.92 Impact Factor
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ABSTRACT: Core sequences necessary for substrate recognition and its inhibition at the PR/p3 site of HTLV-1 protease were clarified for the first time. From the cleavage rates of peptides containing a part of the PR/p3 site, a heptapeptide was found to be the minimal sequence required for substrate recognition. The use of synthetic inhibitors containing hydroxyethylamine dipeptide isostere indicated that a tetrapeptide sequence was necessary to achieve potent inhibition.
Bioorganic & Medicinal Chemistry Letters 08/2006; 16(14):3761-4. · 2.55 Impact Factor
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ABSTRACT: [reaction: see text] The solid-phase Horner-Emmons reaction was successfully applied for the convenient syntheses of olefin-containing protease inhibitors. The isomerization during the solid-phase Horner-Emmons reaction can be minimized simply by the use of an appropriate amount of the base. The synthesized olefin peptides, which have an olefin gamma-amino acid at the scissile site, were found to act as effective inhibitors for the HTLV-1 protease for the first time.
The Journal of Organic Chemistry 01/2006; 70(25):10596-9. · 4.45 Impact Factor
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Yasufumi Kawanaka,
Kaoru Kobayashi,
Shinya Kusuda, Tadashi Tatsumi,
Masayuki Murota,
Toshihiko Nishiyama,
Katsuya Hisaichi,
Atsuko Fujii,
Keisuke Hirai,
Masao Naka,
Masaharu Komeno,
Yshihiko Odagaki,
Hisao Nakai,
Masaaki Toda
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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.
Bioorganic & Medicinal Chemistry 05/2003; 11(8):1723-43. · 2.92 Impact Factor
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Yasufumi Kawanaka,
Kaoru Kobayashi,
Shinya Kusuda, Tadashi Tatsumi,
Masayuki Murota,
Toshihiko Nishiyama,
Katsuya Hisaichi,
Atsuko Fujii,
Keisuke Hirai,
Minoru Nishizaki,
Masao Naka,
Masaharu Komeno,
Hisao Nakai,
Masaaki Toda
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ABSTRACT: The process of discovery and biological evaluation of alpha,beta-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1, 5, 6, 8-12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6, 7, 10, 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1, 6, 10, 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure-activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS.
Bioorganic & Medicinal Chemistry 04/2003; 11(5):689-702. · 2.92 Impact Factor
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Yasufumi Kawanaka,
Kaoru Kobayashi,
Shinya Kusuda, Tadashi Tatsumi,
Masayuki Murota,
Toshihiko Nishiyama,
Katsuya Hisaichi,
Atsuko Fujii,
Keisuke Hirai,
Masao Naka,
Masaharu Komeno,
Hisao Nakai,
Masaaki Toda
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ABSTRACT: 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.
European Journal of Medicinal Chemistry 04/2003; 38(3):277-88. · 3.35 Impact Factor
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Yasufumi Kawanaka,
Kaoru Kobayashi,
Shinya Kusuda, Tadashi Tatsumi,
Masanori Murota,
Toshihiko Nishiyama,
Katsuya Hisaichi,
Atsuko Fujii,
Keisuke Hirai,
Masao Naka,
Masaharu Komeno,
Hisao Nakai,
Masaaki Toda
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ABSTRACT: Dihydropyridin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide inhibition assay. Compounds 1, 4, 5 and 7-11 exhibited potent activity in the inducible nitric oxide (iNOS) inhibition assay. Of these 5, 6, 9 and 10 showed 5- to 11-fold increases in isoform selectivity. Compounds 1, 5, 9 and 10 showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 5 also showed good bioavailability (BA) when given orally.
Bioorganic & Medicinal Chemistry Letters 10/2002; 12(17):2291-4. · 2.55 Impact Factor
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