Pharmacological Properties of JTE-952, an Orally Available and Selective Colony Stimulating Factor 1 Receptor Kinase Inhibitor

Abstract

Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.

JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor

“…We then evaluated the inhibitory effect of orally administered JTE-952 on bone destruction and joint inflammation in the CIA model. JTE-952 was administered before disease onset (days [22][23][24][25][26][27][28][29][30][31][32][33][34][35] and significantly and dose-dependently suppressed the bone destruction score and TRAP-positive cell number in the knee joints at doses of ≥3 mg/kg. The disease severity after treatment with 30 mg/kg JTE-952 was almost identical to that in the normal group, in which arthritis was not induced.…”

“…Numerous small-molecule CSF1R inhibitors have been developed that inhibit both joint inflammation and inflammatory bone erosion in animal models of arthritis, but these are limited by poor kinase selectivity. 21) JTE-952 is a novel, orally available type II kinase inhibitor of CSF1R developed by Japan Tobacco Inc. 22) JTE-952 clearly inhibits human CSF1R kinase activity (at an IC 50 of 11.1 nmol/L) in vitro, with no obvious inhibitory activity against other kinases, except tropomyosin-related kinase A. 23) JTE-952 (≥3 mg/kg administered orally) has an anti-inflammatory effect in vivo in mice, evident as the suppression of CSF1-mediated enhancement of lipopolysaccharide (LPS)induced TNF-α production.…”

Azetidines of pharmacological interest

“…The potent inhibitory activity of JTE‐952 against the 50 kinases was on human KIT (36% inhibition at 1000 nM). [ 76 ]…”

Design, Synthesis, In Silico Studies and In Vitro Anticancer Activity of 3‐(4‐Methoxyphenyl)azetidine Derivatives

“…[18] Moreover, azetidine containing derivatives were found to have a specific inhibitor activity against colony stimulating factor 1 receptor (CSF1R) and also useful in treating various human inflammatory diseases and arthritis. [19] Molecules having substitutions at 3 rd position of azetidine are the utmost important part of various prospective therapeutic molecules. [20] Inspired by the various versatile applications of azetidine derivatives, an initiative was made in search of novel azetidine derivatives to explore more potent and less toxic anticancer medicines.…”

“…Literature survey revealed that several derivatives of azetidine have been reported to show wide range of biological activity such as antibacterial, [9] antiobesity, [10] anticancer, [11] analgesic, [12] dopamine antagonist, [13] antimalarial, [14] antischizophrenic, [15] antioxidant, [16] antidiabetic activities [17] and also useful for the treatment of central nervous system disorders [18] . Moreover, azetidine containing derivatives were found to have a specific inhibitor activity against colony stimulating factor 1 receptor (CSF1R) and also useful in treating various human inflammatory diseases and arthritis [19] . Molecules having substitutions at 3 rd position of azetidine are the utmost important part of various prospective therapeutic molecules [20] …”