Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.
Basic Information
ID: ALA4706694
Journal: Bioorg Med Chem Lett
Title: Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.
Authors: Yamamoto H,Sakai N,Ohte S,Sato T,Sekimata K,Matsumoto T,Nakamura K,Watanabe H,Mishima-Tsumagari C,Tanaka A,Hashizume Y,Honma T,Katagiri T,Miyazono K,Tomoda H,Shirouzu M,Koyama H
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.
CiteXplore: 33609658
DOI: 10.1016/j.bmcl.2021.127858
Patent ID: ┄