Design, synthesis and biological evaluation of novel benzoxaborole derivatives as potent PDE4 inhibitors for topical treatment of atopic dermatitis

• Published in: European journal of medicinal chemistry Vol. 213; p. 113171
• Main Authors: Chu, Zhaoxing, Xu, Qinlong, Zhu, Qihua, Ma, Xiaodong, Mo, Jiajia, Lin, Gaofeng, Zhao, Yan, Gu, Yuanfeng, Bian, Lincui, Shao, Li, Guo, Jing, Ye, Wenfeng, Li, Jiaming, He, Guangwei, Xu, Yungen
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-03-2021
• Subjects: Animals; Atopic dermatitis; Benzoxaborole derivatives; Boron Compounds - chemical synthesis; Boron Compounds - chemistry; Boron Compounds - pharmacology; Calcitriol - analogs & derivatives; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Dermatitis, Atopic - chemically induced; Dermatitis, Atopic - drug therapy; Dermatitis, Atopic - metabolism; Dose-Response Relationship, Drug; Drug Design; Edema - chemically induced; Edema - drug therapy; Edema - metabolism; Female; Guinea Pigs; In vivo efficacy; Isoform specificity; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Molecular Structure; Phosphodiesterase 4 Inhibitors - chemical synthesis; Phosphodiesterase 4 Inhibitors - chemistry; Phosphodiesterase 4 Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Safety; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Isoform specificity; Safety; Atopic dermatitis; Benzoxaborole derivatives; In vivo efficacy
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113171

In this work, a series of structurally novel benzoxaborole derivatives were designed, synthesized and biologically evaluated as PDE4 inhibitors for battling atopic dermatitis (AD). Among them, the majority exhibited superior PDE4B inhibitory activities to that of the lead compound Crisaborole, an approved PDE4 inhibitor. In particular, 72, the most potent PDE4B inhibitor throughout this series, displayed 136-fold improved enzymatic activity (IC50 = 0.42 nM) as compared to Crisaborole (IC50 = 57.20 nM), along with favorable isoform specificity. In the phorbol ester (PMA)-induced mouse ear oedema model, 72 exerted remarkably greater efficacy than Crisaborole at the same dosage (P < 0.05). Moreover, the ointment of 72 exerted dramatically enhanced therapeutic potency than the ointment of Crisaborole (P < 0.05) in the calcipotriol-induced mouse AD model. In addition to the potent in vitro and in vivo activity, 72 displayed favorable safety in the repeated oral dose toxicity study and did not exhibit phototoxicity. With the above attractive biological performance, 72 is worthy of further functional investigation as a novel anti-AD therapeutic agent.
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•Novel PDE4B inhibitors were discovered via structure-based drug design.•SAR study identified compound 72 as the most potent one throughout this series.•Compound 72 showed favorable PDE4 selectivity.•Compound 72 exhibited stronger efficacy in AD mice model than crisaborole.•Compound 72 displayed high safety, and no skin phototoxicity was observed.