Work

New structural scaffolds to enhance the metabolic stability of arginine-derived PAD4 inhibitors

Year: 2025

Type: article

Abstract: Although arginine-derived PAD inhibitors represented by Cl-amidine ( 2 ) 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 ( 3 ), we designed two metabolically stable scaffolds, providing two arginine-derived PAD4 inhibitors ( 7 and 8 ). We evaluated their PAD4 enzyme inhibitory activity in vitro and assessed their metabolic stability using liver microsomal assays. These compounds exhibited PAD4 enzyme inhibitory activity ( 7 , IC 50 = 124.93 ± 10.21 μM; 8 , IC 50 = 46.49 ± 4.46 μM). Hydrolysis of haloacetamidine warheads into hydroxyacetamidine, Compound 7 (t 1/2 > 60 min), significantly improved the metabolic stability of the lead BB-Cl-amidine (t 1/2 = 18.11 min). Compound 8 (t 1/2 > 60 min), the isostere of 7 , 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.

Source: Results in Chemistry

DOI: 10.1016/j.rechem.2025.102162