Neutrophils are the most abundant immune cells. However, neutrophil dysregulation leads to acute and chronic inflammation and is involved in various diseases. The aim of this study was to develop anti-inflammatory agents in human neutrophils. A drug screening was conducted on in-house compounds with the potential to inhibit the respiratory burst, which involves the generation of superoxide anions in human neutrophils. Bioisosteric replacement was then applied to design more active derivatives. The most potent inhibitors of superoxide anion generation activity were compounds 58 and 59, which had IC₅₀ values of 13.30 and 9.06 nM, respectively. The inhibitory effects of 58 and 59 were reversed by H89, a PKA inhibitor. PDE selective screening indicated that the best inhibitory effects were PDE4B1 and PDE4D2, and the inhibitory activities were 83% and 85%, respectively, at a 10 μM concentration of 59. The final molecular simulation experiment highlighted the slightly different binding poses of 58 and 59 in the PDE4 active site. An in vivo pharmacokinetic study revealed that the half-life of 59 was approximately 79 min when using intravenous bolus administration. This work introduced a new class structure of PDE4 inhibitors resulting in potent neutrophil inactivation activity, with the aim of contributing to new anti-inflammatory drug discovery.

中性粒细胞是最丰富的免疫细胞。然而，中性粒细胞失调会导致急性和慢性炎症，并与多种疾病有关。这项研究的目的是开发人类中性粒细胞的抗炎剂。对具有抑制呼吸爆发潜力的内部化合物进行了药物筛选，呼吸爆发涉及人类中性粒细胞中超氧阴离子的产生。然后应用生物等排置换来设计更具活性的衍生物。超氧阴离子产生活性最有效的抑制剂是化合物58和59，其IC ₅₀值分别为13.30和9.06 nM。58和59的抑制作用被PKA抑制剂H89逆转。PDE选择性筛选表明，抑制效果最好的是PDE4B1和PDE4D2，在10 μM浓度59时，抑制活性分别为83%和85% 。最终的分子模拟实验强调了PDE4 活性位点中58和59的结合姿势略有不同。体内药代动力学研究表明，静脉推注给药时， 59的半衰期约为 79 分钟。这项工作引入了 PDE4 抑制剂的新类别结构，可产生有效的中性粒细胞失活活性，旨在促进新的抗炎药物的发现。