Lazzara Phillip R, Moore Terry W
Department of Pharmaceutical Sciences , College of Pharmacy , University of Illinois at Chicago , 833 S. Wood Street , Chicago , IL 60612 , USA . Email:
University of Illinois Cancer Center , University of Illinois at Chicago , 1801 W. Taylor Street , Chicago , IL 60612 , USA.
RSC Med Chem. 2019 Dec 16;11(1):18-29. doi: 10.1039/c9md00396g. eCollection 2020 Jan 1.
Understanding and minimizing oxidative metabolism of aromatic compounds is a key hurdle in lead optimization. Metabolic processes not only clear compounds from the body, but they can also transform parent compounds into reactive metabolites. One particularly useful strategy when addressing metabolically labile or oxidation-prone structures is scaffold-hopping. Replacement of an aromatic system with a more electron-deficient ring system can often increase robustness towards cytochrome P450-mediated oxidation while conserving the structural requirements of the pharmacophore. The most common example of this substitution strategy, replacement of a phenyl ring with a pyridyl substituent, is prevalent throughout the literature; however scaffold-hopping encompasses a much wider scope of heterocycle replacement. This review will showcase recent examples where different scaffold-hopping approaches were used to reduce metabolic clearance or block the formation of reactive metabolites. Additionally, we will highlight considerations that should be made to garner the most benefit from a scaffold-hopping strategy for lead optimization.
理解并尽量减少芳香族化合物的氧化代谢是先导化合物优化过程中的一个关键障碍。代谢过程不仅会将化合物从体内清除，还能将母体化合物转化为活性代谢物。在处理代谢不稳定或易氧化结构时，一种特别有用的策略是骨架跃迁。用电子缺乏程度更高的环系取代芳香体系通常可以提高对细胞色素P450介导的氧化的稳定性，同时保留药效团的结构要求。这种取代策略最常见的例子，即用吡啶基取代苯环，在文献中很普遍；然而，骨架跃迁涵盖了更广泛的杂环取代范围。本综述将展示近期使用不同骨架跃迁方法来减少代谢清除或阻止活性代谢物形成的例子。此外，我们将强调为从骨架跃迁策略中获得最大益处以进行先导化合物优化而应考虑的因素。
