Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC₅₀ values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG_35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.

在这里，我们描述了使用溶液相/相结合的方法从2,4-二氯-3-硝基吡啶快速合成三取代的咪唑并[4,5- b ]吡啶和咪唑并[4,5- c ]吡啶的聚焦库固相化学是治疗自身免疫性疾病的新型潜在抗炎药。结构-活性关系研究，然后进行结构优化，提供了可抑制磷酸二酯酶4（PDE4）且其IC ₅₀值可与咯利普兰相当的命中化合物（17和28），并显示出对磷酸二酯酶7（PDE7）的不同抑制效力。其中，化合物17在所有研究的炎性和自身免疫性疾病动物模型（伴刀豆球蛋白A引起的肝炎，脂多糖引起的内毒素血症，胶原蛋白引起的关节炎和MOG _35-55引起的脑脊髓炎）中显示出有益的作用。另外，腹膜内给药后，化合物17显示出良好的药代动力学特征。它的特点是从腹膜腔快速吸收并且在大鼠中具有相对长的终末半衰期。发现它可以穿透小鼠的脑屏障。进行的实验揭示了在这些疾病条件下PDE7A抑制对PDE4抑制剂功效的影响。