探索吡啶并[3,4-]嘧啶作为人趋化因子受体 CXCR2 的拮抗剂。
Exploration of Pyrido[3,4-]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2.
机构信息
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Department of Microbiology, Immunology and Transplantation-Laboratory of Virology and Chemotherapy, KU Leuven-Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium.
出版信息
Molecules. 2023 Feb 23;28(5):2099. doi: 10.3390/molecules28052099.
Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4-]pyrimidine analogue as a promising CXCR2 antagonist with an IC value of 0.11 µM in a kinetic fluorescence-based calcium mobilization assay. This study aims at exploring the structure-activity relationship (SAR) and improving the CXCR2 antagonistic potency of this pyrido[3,4-]pyrimidine via systematic structural modifications of the substitution pattern. Almost all new analogues completely lacked the CXCR2 antagonism, the exception being a 6-furanyl-pyrido[3,4-]pyrimidine analogue (compound ) that is endowed with similar antagonistic potency as the original hit.
上调的 CXCR2 信号在许多炎症、自身免疫和神经退行性疾病以及癌症中都有发现。因此，CXCR2 拮抗作用是治疗这些疾病的一种很有前途的治疗策略。我们之前通过支架跳跃法，发现一种吡啶并[3,4-]嘧啶类似物作为一种很有前途的 CXCR2 拮抗剂，在基于动力学荧光的钙动员测定中，IC 值为 0.11 µM。本研究旨在通过对取代模式进行系统的结构修饰，探索该吡啶并[3,4-]嘧啶的结构-活性关系（SAR）并提高其对 CXCR2 的拮抗作用。几乎所有的新类似物完全缺乏对 CXCR2 的拮抗作用，只有一个 6-呋喃基-吡啶并[3,4-]嘧啶类似物（化合物 ）具有与原始命中物相似的拮抗作用。
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