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Identification of sulfonylpyrimidines as novel selective aldosterone synthase (CYP11B2) inhibitors.
Meguro, Masaki; Miyauchi, Satoru; Kanao-Arisumi, Yukiko; Naito, Satoru; Suzuki, Kanae; Inoue, Shinichi; Yamada, Keisuke; Homma, Tsuyoshi; Chiba, Kiyoshi; Nara, Futoshi; Furuzono, Shinji.
Affiliation
  • Meguro M; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: meguro.masaki.i2@daiichisankyo.co.jp.
  • Miyauchi S; Technology Division, Technology Business Management Group, Daiichi Sankyo Co., Ltd., 1-12-1, Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan.
  • Kanao-Arisumi Y; Pharmaunion Co., Ltd., 1-23-39 Hiikawa, Jounan-ku, Fukuoka-shi, Fukuoka 814-0153, Japan.
  • Naito S; Site Operations Department, Shinagawa Site Operation Group, Daiichi Sankyo Business Associe Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Suzuki K; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Inoue S; Daiichi Sankyo Inc., 211 Mt. Airy Road, Basking Ridge, NJ 07920, USA.
  • Yamada K; Medical Affairs Division, Medical Affairs Planning Department, Daiichi Sankyo Co., Ltd., 3-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8426, Japan.
  • Homma T; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Chiba K; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Nara F; Shin Nippon Biomedical Laboratories, Ltd., 8-1-28, Akashicho, Chuo-ku, Tokyo 104-0044, Japan.
  • Furuzono S; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Bioorg Med Chem ; 108: 117775, 2024 Jun 15.
Article in En | MEDLINE | ID: mdl-38851000
ABSTRACT
4-[(5-[2-Methyl-5-(methylsulfonyl)pentan-2-yl]sulfonylpyrimidin-4-yl)amino]benzonitrile 2 was identified as a novel potent aldosterone synthase inhibitor. Compound 2 was found to inhibit human CYP11B2 in the nanomolar range, and showed an aldosterone-lowering effect in a furosemide-treated cynomolgus monkey model. Although human CYP11B2 has the high homology sequence with human CYP11B1, compound 2 showed more than 80 times higher selectivity over human CYP11B1 in vitro.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Cytochrome P-450 CYP11B2 / Enzyme Inhibitors / Macaca fascicularis Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2024 Document type: Article Country of publication: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Cytochrome P-450 CYP11B2 / Enzyme Inhibitors / Macaca fascicularis Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2024 Document type: Article Country of publication: United kingdom