Chemical Properties
The p-toluenesulfonic acid salt of brepocitinib exhibits good aqueous solubility (4.84 mg/mL at pH 7.64; >7 mg/mL in simulated gastric fluids). This compound also displayed high passive membrane permeability (mean PAPP = 18.8 × 106 cm/s as determined using Ralph Russ canine kidney cells (RRCK)).
Characteristics
Class: non-receptor tyrosine kinase
Treatment: immunological disorders
Other name: PF-06700841; Brepocitinib
Elimination half-life = 3.8–7.5 h
Protein binding = 39%
Uses
PF-06700841 tosylate salt has been used as an inhibitor of Janus kinase1 (JAK1) to study its therapeutic effect on the adjuvant induced arthritis (AIA) rat model. It has also been used as an inhibitor of interferon-α/β receptor alpha chain (IFNAR1) signaling adaptor tyrosine kinase (2TYK2) in mice.
Biochem/physiol Actions
PF-06700841 prevents IL-23 (interleukin 23) signaling through TYK2 (Tyrosine-protein kinase 2)/JAK1 (Janus kinase 1) inhibition.
Pharmacokinetics
The high oral bioavailability of brepocitinib obtained from rats (83%) is consistent with its high passive permeability and good solubility. The elimination half-life of brepocitinib ranged from 3.8 to 7.5 h after a single oral dose and from 4.9 to 10.7 h after multiple-dose administration. It was eliminated from the body by CYP450-mediated hepatic metabolism (84%) (mainly via CYP3A4) and renal clearance (16%). Oxidation of the N-methyl pyrazole (2) is the major metabolic pathway, followed by N-demethylation (3) and N-dealkylation with loss of pyrazole (4).
Safety
Brepocitinib(PF-06700841) was generally effective and well tolerated in patients with moderate-to-severe plaque psoriasis.
Synthesis
Brepocitinib(PF06700841) can be synthesized as follows :
Add 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (700 mg), HATU (1.02 g, 2.61 mmol) and DIPEA (0.76 mL, 4.34 mmol) to a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (318 mg) in DCM (20 mL);
Stir the reaction at room temperature for 18 hours;
Dilute the reaction with DCM and saturated aqueous ammonium chloride solution;
Separate the organic layer;
Wash the organic layer with ammonium chloride solution;
Concentrate the organic layer in vacuo;
Purify the residue using silica gel column chromatography eluting with 0-12% MeOH and 1% NH4OH in DCM;
Dissolve the residue in DCM;
Wash the residue with saturated aqueous ammonium chloride solution three times;
Collect the organic layer;
Concentrate the organic layer in vacuo;
Dry the organic layer.
