Borhade Sanjay R, Svensson Richard, Brandt Peter, Artursson Per, Arvidsson Per I, Sandström Anja
Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, Biomedical Center, Uppsala University, P.O. Box 574, 751 23 Uppsala (Sweden).
ChemMedChem. 2015 Mar;10(3):455-60. doi: 10.1002/cmdc.201402497. Epub 2015 Jan 28.
Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pKa , lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.
在此，我们展示了含有线性酰基磺酰亚胺酰胺官能团的新型化合物的临床前特性。具体而言，我们研究了9种芳基酰基磺酰亚胺酰胺的pKa、亲脂性、体外代谢稳定性、血浆蛋白结合率、Caco-2细胞通透性和水溶性。与广泛使用的羧酸生物电子等排体相比，根据所研究化合物中的取代模式，酰基磺酰亚胺酰胺的酸性较低且亲脂性更强。重要的是，pKa值（5.9 - 7.6）受氮原子上的取代基和芳基取代基的显著影响。此外，酰基磺酰亚胺酰胺的膜通透性范围从中等到非常高，这与降低的pKa以及低至可忽略不计的外排率相关。我们预计，线性酰基磺酰亚胺酰胺的手性硫中心和两个用于结构多样性的基团将为药物设计以及提高酸性候选药物的口服生物利用度提供新的机会。
