Sussex Drug Discovery Centre, University of Sussex, Brighton BN1 9RH, U.K.
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
J Med Chem. 2021 Aug 12;64(15):11709-11728. doi: 10.1021/acs.jmedchem.1c01115. Epub 2021 Aug 3.
Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of in an setting. These pyrazolo[1,5-]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.
双特异性酪氨酸调节激酶 1A（DYRK1A）在大脑发育过程中调节神经元祖细胞的增殖和分化。因此，DYRK1A 作为治疗神经退行性疾病（包括阿尔茨海默病（AD）和唐氏综合征）的靶点引起了关注。最近，抑制 DYRK1A 被研究作为治疗糖尿病的一种潜在方法，而 DYRK1A 作为细胞周期中介物在肿瘤学适应症中受到关注。结构-活性关系（SAR）分析结合高分辨率 X 射线晶体学导致了一系列具有优异配体效率、良好物理化学性质和对激酶组高度选择性的吡唑并[1,5-]哒嗪抑制剂。化合物 表现出良好的通透性和细胞活性，没有 P-糖蛋白的负担，在 环境中扩展了 的用途。这些吡唑并[1,5-]哒嗪是发现与 DYRK1A 功能相关疾病的新治疗方法的可行先导系列。
