Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5305-9. doi: 10.1016/j.bmcl.2011.07.023. Epub 2011 Jul 14.
A small library of 25 triazole/tetrazole-based sulfonamides have been synthesized and further evaluated for their inhibitory activity against thrombin, trypsin, tryptase and chymase. In general, the triazole-based sulfonamides inhibited thrombin more efficiently than the tetrazole counterparts. Particularly, compound 26 showed strong thrombin inhibition (K(i)=880 nM) and significant selectivity against other human related serine proteases like trypsin (K(i)=729 μM). Thrombin binding affinity of the same compound was determined by ITC and demonstrated that the binding of this new triazole-based scaffold is enthalpically driven, making it a good candidate for further development.
已经合成了一个由 25 个三唑/四唑基磺酰胺组成的小文库，并进一步评估了它们对凝血酶、胰蛋白酶、胰凝乳蛋白酶和糜蛋白酶的抑制活性。一般来说，三唑基磺酰胺对凝血酶的抑制作用比四唑基磺酰胺更有效。特别是，化合物 26 表现出强烈的凝血酶抑制作用（K(i)=880 nM），对其他人类相关丝氨酸蛋白酶如胰蛋白酶（K(i)=729 μM）具有显著的选择性。通过 ITC 测定了同一化合物的凝血酶结合亲和力，并表明该新型三唑基骨架的结合是由焓驱动的，这使其成为进一步开发的良好候选物。
