Identification of TUL01101: A Novel Potent and Selective JAK1 Inhibitor for the Treatment of Rheumatoid Arthritis

Abstract

Janus kinase 1 (JAK1) is a potential target for the treatment of rheumatoid arthritis (RA). In this study, the introduction of a spiro ring with a difluoro-substituted cyclopropionamide resulted in the identification of TUL01101 (compound 36) based on a triazolo[1,5-a]pyridine core of filgotinib. It showed excellent potency on JAK1 with an IC50 value of 3 nM and exhibited more than 12-fold selectivity for JAK2 and TYK2. Whole blood assay also demonstrated the high activity and selectivity (37-fold for JAK2). At the same time, TUL01101 also demonstrated excellent metabolic stability and pharmacokinetics (PK) profiles were assayed in three species (mouse, rat, and dog). Moreover, it has been validated for effective activity in the treatment of RA both in collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models, with low dose and low toxicity. Now, TUL01101 has progressed into phase I clinical trials.

Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis

“…). 17e was synthesized in 49% yield according to the same procedure as 16a using the intermediate 12 (0.25 mmol) and 3-cyanobenzaldehyde (0.5 mmol); 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 9.63 (d, J = 8.7 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J = 4.5 Hz, 1H), 7.78−7.72 (m, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.17 (dd, J = 3.2, 2.2 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 4.86 (d, J = 49.4 Hz, 1H), 4.30−4.14 (m, 1H), 3.63 (s, 2H), 3.06 (t, J = 9.3 Hz, 1H), 2.81−2.77 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.51 (dd, J = 35.7, 12.9 Hz, 1H), 2.34 (t, J = 10.6 Hz, 1H), 1.90 (d, J = 9.7 Hz, 1H), 1.80 (q, J = 10.7 Hz, 1H); 13 1-Benzyl-2,2-dimethylpiperidin-4-amine (30). To a solution of intermediate 27 (1 equiv) in methanol (10 mL) were added ammonium acetate (10 equiv) and 4 Å molecular sieves and stirred for 1 h for the conversion of carbonyl groups of intermediate 27 to amine.…”

“…Nonetheless, it is currently postulated that the pursuit of JAK-selective inhibitors tailored to target specific signals associated with each JAK rather than broadly inhibiting all cytokine signaling holds a significant advantage for achieving toxicity control . For this reason, researchers are developing selective inhibitors , for each JAK to achieve more targeted and effective treatments with fewer side effects. Although further research is necessary to draw definitive conclusions regarding their long-term safety profiles, initial studies have shown that selective inhibitors are generally less toxic than broad-spectrum inhibitors …”

“…Given its versatile nature, selective inhibition of JAK1 provides a more targeted approach to modulating cytokine signaling . This allows specific control of biological functions related to JAK1 without affecting other JAK-dependent signals, which may reduce the risk of side effects as compared with pan-JAK or dual JAK inhibitors . The development of JAK2 inhibitors has gained attention as they have been implicated in the progression of various cancers, including myeloproliferative neoplasms and polycythemia vera .…”

“…32 This allows specific control of biological functions related to JAK1 without affecting other JAKdependent signals, which may reduce the risk of side effects as compared with pan-JAK or dual JAK inhibitors. 30 The development of JAK2 inhibitors has gained attention as they have been implicated in the progression of various cancers, including myeloproliferative neoplasms and polycythemia vera. 33 However, given the involvement of JAK2s in platelet production and myeloid hematopoiesis, 8,9 inhibiting JAK2 in conditions unrelated to its association may lead to side effects linked to these processes.…”

Regioselective Access to 1,2,4-Triazole-Fused N-Heterocycle, Pyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine, via Double Dehydrative Cyclizations

“…1,2,4-Triazole has been widely employed as a key structure of numerous bioactive small molecules (Figure ). Indeed, it is a substructure of many therapeutic agents being developed as well as clinically used medicines such as triazolam, trapidil, and sitagliptin. Despite its prevalence in functional chemicals, 1,2,4-triazole-fused ring systems have been relatively less explored .…”