PDF(Pubmed)
Abstract：
Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.
摘要：
原肌球蛋白受体激酶（Trks）是跨膜受体酪氨酸激酶，命名为TrkA，TrkB,和TrkC，由NTRK1，NTRK2和NTRK3基因编码，分别。由于它们在细胞信号传导途径中的重要作用,这些激酶已经引起了极大的关注并且代表了用于实体瘤治疗的有希望的治疗靶标。第一代TRK抑制剂，即，硫酸拉罗替尼和恩替替尼，分别于2018年和2019年获得临床批准。然而,由于突变引起的耐药性的发展，这些抑制剂的使用受到了极大的限制。幸运的是,第二代Trk抑制剂Repotrectinib(TPX-0005)于2023年11月获得FDA批准,而Selitrectinib(Loxo-195)为这一问题提供了有效的解决方案.另一个基于宏循环的模拟，以及许多其他TRK抑制剂，目前正在临床试验中。三种上市的NTRK融合癌药物中有两种具有吡唑并[1,5-a]嘧啶核，促使药物化学家开发许多新的吡唑并嘧啶基分子，以提高临床应用。本文着重对吡唑并[1,5-a]嘧啶衍生物作为Trk抑制剂的按时间顺序的合成发展和结构-活性关系（SAR）进行了全面综述。本文还将通过促进吡唑并[1,5-a]嘧啶衍生物的结构修饰以合成更有效的新型化学治疗剂作为TRK抑制剂，为在药物化学领域工作的研究人员提供全面的知识和未来的方向。
