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

共 50 条

[31] Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population
Barbato, A
Russo, P
Siani, A
Folkerd, EJ
Miller, MA
Venezia, A
Grimaldi, C
Strazzullo, P
Cappuccio, FP
JOURNAL OF HYPERTENSION, 2004, 22 (10) : 1895 - 1901
[32] Correlations of CYP11B2 gene polymorphisms with eclampsia
Zou, A-X
Zhu, F-X
Jiang, M-X
Bao, D.
EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES, 2020, 24 (20) : 10338 - 10345
[33] CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism
Mulatero, P
Schiavone, D
Fallo, F
Rabbia, F
Pilon, C
Chiandussi, L
Pascoe, L
Veglio, F
HYPERTENSION, 2000, 35 (03) : 694 - 698
[34] Association of aldosterone synthase (CYP11B2 C-344T) gene polymorphism & susceptibility to essential hypertension in a south Indian Tamil population
Rajan, S.
Ramu, P.
Umamaheswaran, G.
Adithan, C.
INDIAN JOURNAL OF MEDICAL RESEARCH, 2010, 132 (04) : 379 - 385
[35] Association of aldosterone synthase CYP11B2 (-344C/T) gene polymorphism with essential hypertension and left ventricular hypertrophy in the Egyptian population
Ghafar, Muhammad Tarek Abdel
CLINICAL AND EXPERIMENTAL HYPERTENSION, 2019, 41 (08) : 779 - 786
[36] Atractylenolide-I covalently binds to CYP11B2, selectively inhibits aldosterone synthesis, and improves hyperaldosteronism
Liu, Wenjuan
Li, Zhenqiang
Chu, Simeng
Ma, Xiaoyao
Wang, Xiaoying
Jiang, Min
Bai, Gang
ACTA PHARMACEUTICA SINICA B, 2022, 12 (01) : 135 - 148
[37] A ubiquitin-proteasome inhibitor bortezomib suppresses the expression of CYP11B2, a key enzyme of aldosterone synthesis
Ito, Ryo
Sato, Ikuko
Tsujita, Tadayuki
Yokoyama, Atsushi
Sugawara, Akira
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2017, 489 (01) : 21 - 28
[38] Genetic polymorphism of CYP11B2 gene and hypertension in Japanese
Tamaki, S
Iwai, N
Tsujita, Y
Kinoshita, M
HYPERTENSION, 1999, 33 (01) : 266 - 270
[39] Polymorphism of CYP11B2 determines salt sensitivity in Japanese
Iwai, Naoharu
Kajimoto, Kazuaki
Tomoike, Hitonobu
Takashima, Naoyuki
HYPERTENSION, 2007, 49 (04) : 825 - 831
[40] Association between aldosterone synthase (CYP11B2)-344C/T polymorphism and atrial fibrillation among Han and Kazak residents of the Xinjiang region
Lu, Wu-Hong
Bayike, Maerjiaen
Liu, Ji-Wen
Wang, Shanshan
Xie, Xiang
Yang, Yu-Chun
Liu, Fen
Li, Na
Liu, Zhi-Qiang
He, Peng-Yi
Muhuyati
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, 2015, 8 (04): : 5513 - 5519

← 1 2 3 4 5 →