Greenwood Nathaniel S, Boyer Zachary W, Ellman Jonathan A, Gnamm Christian
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany.
J Med Chem. 2025 Feb 27;68(4):4079-4100. doi: 10.1021/acs.jmedchem.4c02714. Epub 2025 Jan 9.
While sulfoximines are nowadays a well established functional group for medicinal chemistry, the properties of sulfilimines are significantly less well studied, and no sulfilimine has progressed to the clinic to date. In this account, the physicochemical and in vitro properties of sulfilimines are reported and compared to those of sulfoximines and other more traditional functional groups. Furthermore, the impact on the physicochemical and in vitro properties of real drug scaffolds is studied in two series of sulfilimine-containing analogs of imatinib and hNE inhibitors. We show that sulfilimines can be chemically and configurationally stable under physiologically relevant conditions and that they are basic and highly polar and thus are often beneficial for solubility and metabolic stability, although at the cost of reduced permeability. We conclude that -cyclopropyl,-(hetero)aryl and ,-di(hetero)aryl sulfilimines are so far neglected but potentially valuable S(IV) based pharmacophores that deserve to be considered as part of the medicinal chemistry toolbox.
虽然如今磺胺氧化亚胺是药物化学中一个成熟的官能团，但磺胺亚胺的性质却鲜少得到充分研究，且迄今为止尚无磺胺亚胺进入临床阶段。在本报告中，我们报道了磺胺亚胺的物理化学性质和体外性质，并将其与磺胺氧化亚胺及其他更传统官能团的性质进行了比较。此外，我们在两个系列的含磺胺亚胺的伊马替尼和人中性粒细胞弹性蛋白酶（hNE）抑制剂类似物中研究了其对实际药物支架物理化学性质和体外性质的影响。我们表明，磺胺亚胺在生理相关条件下在化学和构型上可以是稳定的，并且它们呈碱性且极性很高，因此尽管以降低通透性为代价，但通常对溶解度和代谢稳定性有益。我们得出结论，环丙基、（杂）芳基和二（杂）芳基磺胺亚胺是迄今为止被忽视但可能有价值的基于S(IV)的药效基团，值得作为药物化学工具箱的一部分加以考虑。
