Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Bioorg Med Chem Lett. 2021 Apr 15;38:127858. doi: 10.1016/j.bmcl.2021.127858. Epub 2021 Feb 18.
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.
突变激活素受体样激酶 2（ALK2）与纤维发育不良性骨化进展（fibrodysplasia ossificans progressiva）的发病机制有关，使其成为治疗干预的有吸引力的靶点。我们合成了一系列新的双环吡唑，并评估了它们对突变 ALK2 酶的抑制活性，从而确定 8 为最有效的抑制剂。该化合物表现出中等的微粒体代谢稳定性和人 Ether-a-go-go 相关基因（hERG）安全性。在携带突变 ALK2（R206H）的 C2C12 细胞中，8 有效抑制骨形态发生蛋白（BMP）诱导的碱性磷酸酶活性。
