In vivo toxicity and pharmacokinetic features of the Janus kinase 3 inhibitor WHI-P131 [4-(4 ' hydroxyphenyl)-amino-6,7-dimethoxyquinazoline]

4-(4'Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) is a potent a nd selective inhibitor of the Janus kinase 3, which triggers apoptosis in h uman acute lymphoblastic leukemia (ALL) cells. In this preclinical study, w e evaluated the pharmacokinetics and toxicity of WHI-P131 in rats, mice, an d cynomolgus monkeys, Following i.v. administration, the terminal eliminati on half-life of WHI-P131 was 73.2 min in rats, 103.4 min in mice, and 45.0 min in monkeys. The i.v. administered WHI-P131 showed a very wide tissue di stribution in mice. Following i.p. administration, WHI-P131 was rapidly abs orbed in both rats and mice, and the time to reach the maximum plasma conce ntration (t(max)) was 24.8 min in rats and 10.0 min in mice. Subsequently, WHI-P131 was eliminated with a terminal elimination half-life of 51.8 min i n rats and 123.6 min in mice. The estimated i.p. bioavailability was 95% fo r rats, as well as for mice, WHI-P131 was quickly absorbed after oral admin istration in mice with a t(max) of 5.8 min, but its oral bioavailability wa s relatively low (29.6%), The elimination half-life of WHI-P131 after oral administration was 297.6 min. WHI-P131 was not acutely toxic to mice at sin gle i.p. bolus doses ranging from 0.5-250 mg/kg, Two cynomolgus monkeys tre ated with 20 mg/kg WHI-P131 and one cynomolgus monkey treated with 100 mg/k g WHI-P131 experienced no side effects. Plasma samples from WHI-P131-treate d monkeys exhibited potent antileukemic activity against human ALL cells in vitro. To our knowledge, this is the first preclinical toxicity and pharma cokinetic study of a Janus kinase 3 inhibitor, Further development of WHI-P 131 may provide the basis for nea and effective treatment programs for rela psed ALL in clinical settings.