Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties
Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties
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DOI：
10.1002/cmdc.201402497
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发表时间：
2015-03-01
期刊：
影响因子：
3.4
通讯作者：
Sandstroem, Anja
中科院分区：
文献类型：
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作者：
Borhade, Sanjay R.;Svensson, Richard;Sandstroem, Anja
在这里，我们提出了新的化合物的临床前表征含有线性酰基磺酰亚胺酰胺功能。具体而言，我们研究了9种芳基酰基磺酰亚胺酰胺的pK（a）、亲脂性、体外代谢稳定性、血浆蛋白结合、Caco-2渗透性和水溶性。与广泛使用的羧酸生物电子等排体相比，酰基磺酰亚胺酰胺被发现是较少的酸性和更多的亲脂性取决于在所研究的化合物中的取代模式。重要的是，pKa值（5.9-7.6）受到氮原子上的取代基和芳基取代基的显著影响。此外，酰基磺酰亚胺酰胺显示膜渗透性范围从中等到非常高，这与降低的pKa和低至可忽略的外排率相关。我们预见，手性硫中心和两个手柄的线性酰基磺酰亚胺酰胺的结构多样性将提供新的机会，药物设计和提高口服生物利用度的酸性候选药物。
Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), 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.