化学
吞噬作用
调理素
吡唑
抗体
免疫系统
IC50型
外周血单个核细胞
体外
立体化学
生物化学
药理学
免疫学
医学
作者
Meena K. Purohit,Sai Kumar Chakka,Iain Scovell,Anton Neschadim,Angélica M. Bello,Noruê Salum,Yulia Katsman,Madeleine C. Bareau,Donald R. Branch,Lakshmi P. Kotra
标识
DOI:10.1016/j.bmc.2014.03.016
摘要
Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure–activity relationship of the bis-pyrazole class of molecules with –C–C–, –C–N– and –C–O– linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N1 positions of the bivalent pyrazole core to be important for the inhibitory activity.
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