Characteristics
Class: non-receptor tyrosine kinase
Treatment: rheumatoid arthritis
Elimination half-life = 9.4 ± 7.4 h
Protein binding = 73–75%
Uses
Peficitinib can be used in therapeutic use and biological study of codrug and preparation of bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators.
Biological Activity
peficitinib (asp015k) is an oral janus kinase (jak) inhibitor. it inhibits enzyme activities of jak1, jak2, jak3 and tyk2 with ic50 values of 3.9, 5.0, 0.71 and 4.8 nmol/l, respectively. it showed moderate selectivity for jak3 inhibition [1].jak family of non-receptor protein tyrosine kinases includes jak1, jak2, jak3 and tyrosine kinase 2 (tyk2). jak1, jak2, jak3 and tyk2 are critically important in haematopoietic cells and immune cells [1].erythropoietin regulates haematopoiesis (the production of blood cells) [2]. treatment with asp015k inhibited the human t-cell proliferation induced by il-2. and this effect was greater than the effect to inhibit epo-induced human erythroleukemia cell proliferation. in human whole blood, asp015k concentration-dependently inhibited stat5 phosphorylation (pstat5) [3].in healthy volunteers, stat5-p was dose-dependently inhibited by asp015k. when the doses of asp015k were 60, 120, 200, or 300 mg, the mean peak percentage inhibitions of stat5-p were 84%, 85%, 92%, and 93%, respectively. plasma asp015k inhibited stat5-p with an ec50 value of 48 ng/ml, a shape factor (γ) of ~1.2, and an estimated emax close to 100%. on days 1, 7, and 14, at ~2 hours after treatment with asp015k at multiple doses, the peak of median percentage of stat5-p inhibition appeared [4].
Enzyme inhibitor
This orally bioavailable JAK inhibitor and anti-rheumatoid arthritis drug (FW = 326.39 g/mol; CAS 944118-01-8; Solubility: 200 mM in DMSO), also named ASP015K, JNJ-54781532, and trans-4-[[5-hydroxy-2- adamantyl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, targets Janus Kinase JAK1, JAK2, JAK3 and the nonreceptor tyrosine kinase Tyk2 enzyme with IC50 values of 3.9, 5.0, 0.71 and 4.8 nM, respectively. Itsselectively suppress JAK3 or JAK1/2, respectively, may explain the weaker effects on red blood cells and platelets reported to be caused by JAK2 inhibition. Moreover, peficitinib improves symptoms in RA animal models after once-daily oral administration and demonstrates dosedependent improvement in psoriatic disease activities in a 6-week phase IIa study. The terminal mean half-life of peficitinib is 7–13 hours in pharmacological studies with healthy subjects
Metabolism
Peficitinib exhibited low aqueous solubility (≤0.1 mg/mL at pH 7) and modest cell permeability. It also showed moderate oral bioavailability in rats (46%) and monkeys (19%). In healthy volunteers, a single oral dose of 150 mg peficitinib showed an elimination half-life of 9.4 h and high clearance (CL/F = 85.7 L/h, 78% of human hepatic blood flow = 109 L/h for 70 kg body weight). Following oral administration, the major metabolites in humans were the sulfate conjugate 9 and N-methyl conjugate 11 via human sulfotransferase SULT2A1 and nicotinamide N-methyltransferase (NNMT). Peficitinib was cleared through multiple pathways (renal and possibly biliary excretion, and metabolism) with no prevalent single mechanism.
References
[1]. takeuchi t, tanaka y, iwasaki m, et al. efficacy and safety of the oral janus kinase inhibitor peficitinib (asp015k) monotherapy in patients with moderate to severe rheumatoid arthritis in japan: a 12-week, randomised, double-blind, placebo-controlled phase iib study. annals of the rheumatic diseases, 2015: annrheumdis-2015-208279.
[2]. digicaylioglu m, lipton sa. erythropoietin-mediated neuroprotection involves cross-talk between jak2 and nf-κb signalling cascades. nature, 2001, 412(6847): 641-647.
[3]. yamazaki s, morio h, inami m, et al. thu0101 asp015k: a novel jak inhibitor demonstrated potent efficacy in adjuvant-induced arthritis model in rats. annals of the rheumatic diseases, 2013, 72(suppl 3): a197-a197.
[4]. zhu t, valluri u, lewand m, et al. thu0256 pharmacodynamics of asp015k, a novel janus kinase inhibitor, in healthy volunteers. annals of the rheumatic diseases, 2013, 72(suppl 3): a252-a252.
