Jia Yijiang, Bahraminejad Sina, Jiang Chenyao, Taledaohan Ayijiang, Ma Dejian, Jiang Jianxiong, Wang Yuji, Liu Jiawang
Medicinal Chemistry Core, Office of Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Results Chem. 2025 May;15. doi: 10.1016/j.rechem.2025.102162. Epub 2025 Feb 28.
Although arginine-derived PAD inhibitors represented by Cl-amidine () showed strong inhibition of PAD4 enzymes and exhibited efficacies in a variety of cellular assays and animal studies, their metabolic instability is a significant challenge for pre-clinical and clinical research. On the basis of the structure of a well-known PAD4 inhibitor BB-Cl-amidine (), we designed two metabolically stable scaffolds, providing two arginine-derived PAD4 inhibitors ( and ). We evaluated their PAD4 enzyme inhibitory activity and assessed their metabolic stability using liver microsomal assays. These compounds exhibited PAD4 enzyme inhibitory activity (, IC = 124.93 ± 10.21 μM; , IC = 46.49 ± 4.46 μM). Hydrolysis of haloacetamidine warheads into hydroxyacetamidine, Compound (t > 60 min), significantly improved the metabolic stability of the lead BB-Cl-amidine (t = 18.11 min). Compound (t > 60 min), the isostere of , also displayed enhanced metabolic stability. Therefore, these two structural scaffolds represent promising new leads for stable PAD4 inhibitors and valuable tools for exploring the reactive cavity of PAD enzymes.
尽管以氯脒（）为代表的精氨酸衍生的PAD抑制剂对PAD4酶表现出强烈的抑制作用，并在各种细胞试验和动物研究中显示出疗效，但其代谢不稳定性对临床前和临床研究来说是一个重大挑战。基于一种著名的PAD4抑制剂BB-氯脒（）的结构，我们设计了两种代谢稳定的支架，得到了两种精氨酸衍生的PAD4抑制剂（和）。我们评估了它们对PAD4酶的抑制活性，并使用肝微粒体试验评估了它们的代谢稳定性。这些化合物表现出对PAD4酶的抑制活性（，IC = 124.93 ± 10.21 μM；，IC = 46.49 ± 4.46 μM）。卤代脒弹头水解为羟基脒，化合物（t > 60分钟）显著提高了先导化合物BB-氯脒（t = 18.11分钟）的代谢稳定性。化合物（t > 60分钟），即的电子等排体，也表现出增强的代谢稳定性。因此，这两种结构支架代表了稳定的PAD4抑制剂的有前景的新先导化合物，也是探索PAD酶反应腔的有价值工具。
