Discovery of selective JAK1/2 inhibitor H018, a phase II agent with demonstrated preclinical anti-rheumatoid arthritis activity

Haifeng Zhu; Shuai Li; Hongfan Wang; Mei Su; Jing Yang; Peng Wang

doi:10.1016/j.ejmech.2026.118729

Discovery of selective JAK1/2 inhibitor H018, a phase II agent with demonstrated preclinical anti-rheumatoid arthritis activity

Eur J Med Chem. 2026 May 5:309:118729. doi: 10.1016/j.ejmech.2026.118729. Epub 2026 Mar 2.

Authors

Haifeng Zhu¹, Shuai Li², Hongfan Wang², Mei Su³, Jing Yang⁴, Peng Wang⁵

Affiliations

¹ Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Carephar Pharmaceutical Co., Ltd, Nanjing, China.
² Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China.
³ Jiangsu Carephar Pharmaceutical Co., Ltd, Nanjing, China.
⁴ Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: yangjing@cpu.edu.cn.
⁵ Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: wangpeng@cpu.edu.cn.

PMID: 41795417
DOI: 10.1016/j.ejmech.2026.118729

Abstract

Janus kinase (JAK) inhibitors represent a class of oral therapeutics for rheumatoid arthritis (RA), demonstrating superior clinical efficacy compared to conventional disease-modifying antirheumatic drugs (DMARDs). However, pan-JAK inhibitors are associated with side effects such as infections and hematologic toxicity, and selective JAK inhibitors exhibit diminished efficacy. Guided by the dual mechanism of JAK1 selectivity driving efficacy and JAK2 inhibition to enhance anti-inflammatory effects, we employed rational drug design to develop the highly selective JAK1/2 inhibitor H018 (RAI-20), intending to improve the drug safety while simultaneously managing adverse effects within a reasonable range. Compound RAI-20 exhibited significantly optimized targeting properties, with kinase inhibitory activity and isoform subtype selectivity comprehensively surpassing clinically approved JAK1 inhibitor Filgotinib, thereby establishing a novel strategic strategy for JAK1/2 inhibitor design. Notably, compound RAI-20 demonstrated distinct advantages in key pharmacokinetic and safety assessment parameters, including enhanced plasma stability, significantly improved systemic exposure (AUC) and prolonged duration of half-life. Furthermore, RAI-20 elicited potent, dose-dependent protection against RA in the collagen-induced arthritis (CIA) model, and its efficacy exceeds some marketed JAK inhibitors. Currently, compound RAI-20 has progressed to Phase II clinical trials and is poised to be a potential RA treatment option that combines high efficacy with low toxicity.

Keywords: Clinical phase II; Drug design; Inhibitors; JAK1/2; Rheumatoid arthritis.

MeSH terms

Animals
Antirheumatic Agents* / chemical synthesis
Antirheumatic Agents* / chemistry
Antirheumatic Agents* / pharmacology
Arthritis, Experimental / drug therapy
Arthritis, Experimental / metabolism
Arthritis, Rheumatoid* / drug therapy
Arthritis, Rheumatoid* / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Janus Kinase 1* / antagonists & inhibitors
Janus Kinase 1* / metabolism
Janus Kinase 2* / antagonists & inhibitors
Janus Kinase 2* / metabolism
Male
Mice
Molecular Structure
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Protein Kinase Inhibitors* / therapeutic use
Rats
Structure-Activity Relationship

Substances

Janus Kinase 1
Janus Kinase 2
Protein Kinase Inhibitors
Antirheumatic Agents
JAK1 protein, human