a ICOA, UMR CNRS 7311 , University of Orleans , Orleans , France.
b UMR 1253, iBrain , Université de Tours, Inserm , Tours , France.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1-7. doi: 10.1080/14756366.2018.1501043.
A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C-H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC values of 0.409 µM and an excellent selectivity versus COX-1. Radiolabeling of this most potent derivative [F]16 was achieved after boron ester release and the tracer was evaluated in vivo in a rat model of neuroinflammation. All chemistry, radiochemistry and biological experimental data are discussed.
开发了一系列在（氮杂）吲唑系列中对 COX-2 酶表现出高亲和力和选择性的新型衍生物。在吲唑和氮杂吲唑系列中，分别建立了一条涉及微波辐射下的溴化/芳基化序列和直接 C-H 活化的短合成路线。进行了体外测定，并对这些支架进行了结构修饰，得到了化合物 16，其对 COX-2 具有有效的抑制活性，IC 值为 0.409 µM，对 COX-1 具有极好的选择性。在硼酯释放后，对这种最有效的衍生物 [F]16 进行了放射性标记，并在神经炎症的大鼠模型中进行了体内评估。讨论了所有的化学、放射化学和生物学实验数据。
