Jiang Jian-Kang, Huang Xiuli, Shamim Khalida, Patel Paresma R, Lee Arthur, Wang Amy Q, Nguyen Kimloan, Tawa Gregory, Cuny Gregory D, Yu Paul B, Zheng Wei, Xu Xin, Sanderson Philip, Huang Wenwei
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA.
Bioorg Med Chem Lett. 2018 Nov 1;28(20):3356-3362. doi: 10.1016/j.bmcl.2018.09.006. Epub 2018 Sep 6.
The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.
吡唑并[1,5 - a]嘧啶类化合物LDN - 193189是激活素受体样激酶2（ALK2）的强效抑制剂，但对高度同源的ALK3无选择性，且在激酶组中仅表现出适度的选择性。在此，我们描述了通过用4 -（氨磺酰基）萘基取代喹啉基发现了一系列新型的强效且选择性的ALK2抑制剂，得到的ALK2抑制剂不仅对ALK3具有出色的区分性，而且在激酶组中具有高选择性。此外，优化后的化合物23表现出良好的吸收、分布、代谢和排泄（ADME）及体内药代动力学性质。
