Novikova Daria, Vorona Svetlana, Zenina Anastasiya, Grigoreva Tatyana, Tribulovich Vyacheslav
Laboratory of Molecular Pharmacology, St. Petersburg State Institute of Technology, St. Petersburg 190013, Russia.
Molecules. 2025 May 22;30(11):2258. doi: 10.3390/molecules30112258.
Pyrazolo[1,5-a]pyrimidine is a nitrogen-containing fused heterocycle that imitates the nitrogenous base adenine with varying degrees of reliability. This fact determines its frequent use in drug design, including the development of ATP-competitive kinase inhibitors. These include dorsomorphin which shows compromised kinase selectivity but is still widely used as an AMPK inhibitor. ATP-binding pockets of many proteins have a fairly conservative spatial structure and there is a high probability of obtaining a compound with low target selectivity during drug development. In the case of a common scaffold, the careful selection of side substituents that determine the activity and selectivity of the final compound plays an important role. In this work, a convergent strategy for the synthesis of dorsomorphin and its close analogs was developed and implemented. The resulting small series of compounds is distinguished by the maximum possible diversification and allows for an assessment of the biological activity towards AMPK. An original route to obtain variants of the phenoxy-alkylamine moiety of dorsomorphin via the Mitsunobu reaction will be useful for generating targeted-focused libraries of ATP-competitive kinase inhibitors and highly active receptor ligands.
吡唑并[1,5 - a]嘧啶是一种含氮稠合杂环，它能不同程度地可靠模拟含氮碱基腺嘌呤。这一事实决定了它在药物设计中经常被使用，包括ATP竞争性激酶抑制剂的开发。其中包括多司莫德，它表现出激酶选择性受损，但仍被广泛用作AMPK抑制剂。许多蛋白质的ATP结合口袋具有相当保守的空间结构，在药物开发过程中很有可能获得具有低靶点选择性的化合物。对于常见的骨架结构，精心选择决定最终化合物活性和选择性的侧链取代基起着重要作用。在这项工作中，开发并实施了一种合成多司莫德及其类似物的汇聚策略。所得的一小系列化合物具有最大可能的多样性，并能够评估其对AMPK的生物活性。通过 Mitsunobu反应获得多司莫德苯氧基 - 烷基胺部分变体的原始路线，将有助于生成ATP竞争性激酶抑制剂和高活性受体配体的靶向聚焦文库。
