944118-01-8

Class: non-receptor tyrosine kinase
Treatment: rheumatoid arthritis
Elimination half-life = 9.4 ± 7.4 h
Protein binding = 73–75%

Peficitinib can be used in therapeutic use and biological study of codrug and preparation of bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators.

Smyraf^TM

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].

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

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.

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[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.