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.

在此，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咪唑并[4,5- b ]吡啶和咪唑并[4,5- c ]吡啶的重点库。固相化学作为治疗自身免疫性疾病的新的潜在抗炎剂。结构-活性关系研究，随后进行结构优化，提供了抑制磷酸二酯酶4 (PDE4)的命中化合物( 17和28 )，其IC ₅₀值与咯利普兰相当，并对磷酸二酯酶7 (PDE7)表现出不同的抑制效力。其中，化合物17在所有研究的炎症和自身免疫性疾病（刀豆蛋白A诱导的肝炎、脂多糖诱导的内毒素血症、胶原诱导的关节炎和MOG _35-55诱导的脑脊髓炎）动物模型中均显示出有益作用。此外，化合物17在腹膜内给药后表现出良好的药代动力学特征；其特点是从腹膜腔吸收快，在大鼠体内的终末半衰期相对较长。人们发现它可以穿透小鼠的脑屏障。所进行的实验揭示了 PDE7A 抑制对 PDE4 抑制剂在这些疾病中的功效的影响。