Based on the previously published pyrazolopyridine-based hit compound for which negative allosteric modulation of both CXCR3 and CXCR4 receptors was disclosed, we designed, synthesized and biologically evaluated a set of novel, not only negative, but also positive allosteric modulators with preserved pyrazolopyridine core. Compound 9e is a dual negative modulator, inhibiting G protein activity of both receptors. For CXCR4 receptor para-substituted aromatic group of compounds distinguishes between negative and positive modulation. Para-methoxy substitution leads to functional antagonism, while para-chloro triggers agonism. Additionally, we discovered that chemotaxis is not completely correlated with G protein pathways. This is the first work in which we have on a series of compounds successfully demonstrated that it is possible to produce selective as well as dual-acting modulators of chemokine receptors, which is very promising for future research in the field of discovery of selective or dual modulators of chemokine receptors.

基于先前公开的基于吡唑并吡啶的命中化合物，针对该化合物公开了CXCR3和CXCR4受体的负变构调节作用，我们设计，合成和生物学评估了一组新颖的，不仅具有阴性而且具有正吡咯并吡啶核心的正变构调节剂。化合物9e是双重负调节剂，抑制两个受体的G蛋白活性。对于CXCR4受体，化合物的对位取代的芳族基团区分负调节和正调节。对甲氧基取代导致功能拮抗作用，而对-氯触发激动作用。此外，我们发现趋化性与G蛋白途径并不完全相关。这是我们对一系列化合物成功进行的第一项工作，成功地证明了它可能产生趋化因子受体的选择性和双重作用调节剂，这对于发现选择性或双重作用的领域的未来研究非常有前途趋化因子受体的调节剂。