Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva

被引：9

作者：

Yamamoto, Hirofumi ^{[1
]}

Sakai, Naoki ^{[2
]}

Ohte, Satoshi ^{[3
]}

Sato, Tomohiro ^{[4
]}

Sekimata, Katsuhiko ^{[1
]}

Matsumoto, Takehisa ^{[2
]}

Nakamura, Kana ^{[2
]}

Watanabe, Hisami ^{[2
]}

Mishima-Tsumagari, Chiemi ^{[2
]}

Tanaka, Akiko ^{[2
]}

Hashizume, Yoshinobu ^{[5
]}

Honma, Teruki ^{[4
]}

Katagiri, Takenobu ^{[6
]}

Miyazono, Kohei ^{[7
]}

Tomoda, Hiroshi ^{[3
]}

Shirouzu, Mikako ^{[2
]}

Koyama, Hiroo ^{[1
]}

机构：

[1] RIKEN Ctr Sustainable Resource Sci, Drug Discovery Chem Platform Unit, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

[2] RIKEN Ctr Biosystems Dynam Res, Drug Discovery Struct Biol Platform Unit, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan

[3] Kitasato Univ, Grad Sch Pharmaceut Sci, Dept Microbial Chem, Minato Ku, 5-9-1 Shirokane, Tokyo 1088641, Japan

[4] RIKEN Ctr Biosyst Dynam Res, Drug Discovery Computat Chem Platform Unit, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan

[5] RIKEN Program Drug Discovery & Med Technol Platfo, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

[6] Saitama Med Univ, Res Ctr Genom Med, Div Biomed Sci, 1397-1 Yamane, Hidaka, Saitama 3501241, Japan

[7] Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 38卷

关键词：

Fibrodysplasia ossificans progressiva (FOP); Activin receptor-like kinase-2 (ALK2); Bicyclic pyrazole derivatives;

D O I：

10.1016/j.bmcl.2021.127858

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-gogo related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity.

引用

页数：5

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