Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva. (15th April 2021)

• Record Type: Journal Article
• Authors: Yamamoto, Hirofumi; Sakai, Naoki; Ohte, Satoshi; Sato, Tomohiro; Sekimata, Katsuhiko; Matsumoto, Takehisa; Nakamura, Kana; Watanabe, Hisami; Mishima-Tsumagari, Chiemi; Tanaka, Akiko; Hashizume, Yoshinobu; Honma, Teruki; Katagiri, Takenobu; Miyazono, Kohei; Tomoda, Hiroshi; Shirouzu, Mikako; Koyama, Hiroo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 38(2021)
• Publication Date: 2021-04-15
• Subjects: ALK2 activin receptor-like kinase-2 -- ALP alkaline phosphatase -- BMP bone morphogenetic protein -- DIPG diffuse intrinsic pontine glioma -- DMF N, N-dimethylformamide -- FOP fibrodysplasia ossificans progressiva -- Herg human ether-a-go-go related gene -- MDCK Madin-Darby canine kidney cells -- SAR structure-activity relationship; Fibrodysplasia ossificans progressiva (FOP) -- Activin receptor-like kinase-2 (ALK2) -- Bicyclic pyrazole derivatives; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127858
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity.