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

被引：1

作者：

Meguro, Masaki ^{[1
]}

Miyauchi, Satoru ^{[2
]}

Kanao-Arisumi, Yukiko ^{[3
]}

Naito, Satoru ^{[4
]}

Suzuki, Kanae ^{[1
]}

Inoue, Shinichi ^{[5
]}

Yamada, Keisuke ^{[6
]}

Homma, Tsuyoshi ^{[1
]}

Chiba, Kiyoshi ^{[1
]}

Nara, Futoshi ^{[7
]}

Furuzono, Shinji ^{[1
]}

机构：

[1] Daiichi Sankyo Co Ltd, Shinagawa R&D Ctr, 1-2-58 Hiromachi,Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, Technol Div, Technol Business Management Grp, 1-12-1 Shinomiya, Hiratsuka, Kanagawa 2540014, Japan

[3] Pharmaun Co Ltd, 1-23-39 Hiikawa,Jounan Ku, Fukuoka, Fukuoka 8140153, Japan

[4] Daiichi Sankyo Business Associe Co Ltd, Site Operat Dept, Shinagawa Site Operat Grp, 1-2-58 Hiromachi,Shinagawa Ku, Tokyo 1408710, Japan

[5] Daiichi Sankyo Inc, 211 Mt Airy Rd, Basking Ridge, NJ 07920 USA

[6] Daiichi Sankyo Co Ltd, Med Affairs Div, Med Affairs Planning Dept, 3-5-1 Nihonbashi Honcho,Chuo Ku, Tokyo 1038426, Japan

[7] Shin Nippon Biomed Labs Ltd, 8-1-28 Akashicho,Chuo Ku, Tokyo 1040044, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2024年 / 108卷

关键词：

Aldosterone; Aldosterone synthase inhibitor; Sulfone; Amino-pyrimidine; IN-VIVO ACTIVITY; POTENTIAL TREATMENTS; DISCOVERY; LCI699; THIOLS;

D O I：

10.1016/j.bmc.2024.117775

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：15

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