Identification of sulfonylpyrimidines as novel selective aldosterone synthase (CYP11B2) inhibitors

  • Bioorg Med Chem. 2024 Jun 15:108:117775. doi: 10.1016/j.bmc.2024.117775.
Masaki Meguro  1 ,  Satoru Miyauchi  2 ,  Yukiko Kanao-Arisumi  3 ,  Satoru Naito  4 ,  Kanae Suzuki  5 ,  Shinichi Inoue  6 ,  Keisuke Yamada  7 ,  Tsuyoshi Homma  5 ,  Kiyoshi Chiba  5 ,  Futoshi Nara  8 ,  Shinji Furuzono  5
Affiliations
  • 1. Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. Technology Division, Technology Business Management Group, Daiichi Sankyo Co., Ltd., 1-12-1, Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan.
  • 3. Pharmaunion Co., Ltd., 1-23-39 Hiikawa, Jounan-ku, Fukuoka-shi, Fukuoka 814-0153, Japan.
  • 4. Site Operations Department, Shinagawa Site Operation Group, Daiichi Sankyo Business Associe Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 5. Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 6. Daiichi Sankyo Inc., 211 Mt. Airy Road, Basking Ridge, NJ 07920, USA.
  • 7. Medical Affairs Division, Medical Affairs Planning Department, Daiichi Sankyo Co., Ltd., 3-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8426, Japan.
  • 8. Shin Nippon Biomedical Laboratories, Ltd., 8-1-28, Akashicho, Chuo-ku, Tokyo 104-0044, Japan.
PMID: 38851000 DOI: 10.1016/j.bmc.2024.117775
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.

Keywords
Aldosterone; Aldosterone synthase inhibitor; Amino-pyrimidine; CYP11B1; CYP11B2; Sulfone.
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