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Kazutaka Tachibana,
Ikuhiro Imaoka,
Hitoshi Yoshino, Nobuaki Kato,
Mitsuaki Nakamura,
Masateru Ohta,
Hiromitsu Kawata,
Kenji Taniguchi,
Nobuyuki Ishikura,
Masahiro Nagamuta,
Etsuro Onuma,
Haruhiko Sato
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ABSTRACT: Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7alpha of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17alpha-methyltestosterone gave compound 14, which showed weak pure antagonistic activity. Optimization of the side chain by the insertion of a phenyl ring led to compounds 22 and 28-30, which showed pure antagonistic activities at submicromolar concentrations. The structure-activity relationships were clarified.
Bioorganic & Medicinal Chemistry Letters 11/2007; 17(20):5573-6. · 2.55 Impact Factor
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Kazutaka Tachibana,
Ikuhiro Imaoka,
Hitoshi Yoshino,
Takashi Emura,
Hirohumi Kodama,
Yoshiyuki Furuta, Nobuaki Kato,
Mitsuaki Nakamura,
Masateru Ohta,
Kenji Taniguchi,
Nobuyuki Ishikura,
Masahiro Nagamuta,
Etsuro Onuma,
Haruhiko Sato
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ABSTRACT: A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.
Bioorganic & Medicinal Chemistry 01/2007; 15(1):174-85. · 2.92 Impact Factor
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Yoshitake Kanbe,
Myung-Hwa Kim,
Masahiro Nishimoto,
Yoshihito Ohtake, Nobuaki Kato,
Toshiaki Tsunenari,
Kenji Taniguchi,
Iwao Ohizumi,
Shin-ichi Kaiho,
Kazumi Morikawa,
Jae-Chon Jo,
Hyun-Suk Lim,
Hak-Yeop Kim
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ABSTRACT: In order to develop pure antiestrogens, a series of 7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman and 7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman derivatives with sulfoxide containing side chains at the 4-position were designed, synthesized, and evaluated. Among them, compounds 14b and 24b functioned as pure antiestrogens with the ability to downregulate ER, and their in vitro and in vivo antiestrogen activities were similar to those of ICI182,780. In addition, the structure-activity relationship indicated that the (3RS,4RS)-configuration between the 3- and 4-position, the methyl group at the 3-position, the 9-methylene chain between the scaffold and the sulfoxide moiety, and the terminal perfluoroalkyl moiety play an important role in increasing estrogen receptor binding and oral antiestrogen activities.
Bioorganic & Medicinal Chemistry 08/2006; 14(14):4803-19. · 2.92 Impact Factor
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Kazuki Shimizu,
Akira Kawase,
Tsuyoshi Haneishi,
Yasuharu Kato,
Kazutomo Kinoshita,
Masayuki Ohmori,
Yoshiyuki Furuta,
Takashi Emura, Nobuaki Kato,
Tetsuya Mitsui,
Koji Yamaguchi,
Keiichi Morita,
Nobuo Sekiguchi,
Tessai Yamamoto,
Tomochika Matsushita,
Shin Shimaoka,
Atsuko Sugita,
Kazumi Morikawa
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ABSTRACT: Design, synthesis, and in vitro and in vivo evaluation of a series of antipsoriatic antedrugs having 16-en-22-oxa-vitamin D3 are described. Among the seven compounds examined, two are promising: ester 5c and amide 5f, both of which exhibit greater potent antiproliferation activity with lessened calcemic activity than the presently prescribed maxacalcitol (2).
Bioorganic & Medicinal Chemistry Letters 07/2006; 16(12):3323-9. · 2.55 Impact Factor
