JAK3-IN-6 is irreversible Janus Associated Kinase 3 (JAK3) inhibitor, with an IC50 of 0.15 nM

JAK3:0.15 nM

a potent inhibitor of JAK3 (0.15 nM) was 4300-fold selective for JAK3 over JAK1 in enzyme assays, 67-fold (IL-2 vs. IL-6) or 140-fold (IL-2 vs. EPO or GMCSF) selective in cellular reporter assays and >35-fold selective in human PBMC assays (IL-7 vs. IL-6 or GMCSF). In vivo, selective JAK3 inhibition was sufficient to block the development of inflammation in a rat model of Rheumatoid Arthritis, while sparing hematopoiesis.

Female Lewis rats were purchased and housed . 48 rats were divided into six groups (n=8/group). Group 1 were drug-na?ve i.e. no compounds were administered throughout the study. On the afternoon of Day 1 (4pm), ABT or vehicle (1 ml/kg p.o.) was administered to Groups 2-5. Days 2-11 (8 am), each animal in Groups 2-5 were administered ABT 10 mpk qd (1 ml/kg p.o.), immediately followed by either vehicle or compound at 5ml/kg p.o. Group 6 animals received vehicle only (5 ml/kg p.o.). Days 2-11 (4 pm) Groups 2-5 were administered vehicle or compound at 5 ml/kg p.o. Animals were monitored and weighed throughout the study. On Day 10, under isoflurane anesthesia, 3 animals from Groups 2-6 were bled via the jugular vein for PK analysis at 4 and 8 h post-8 am dose. On Day 11, blood samples were collected, as described above, at 0 (16 h post-Day 10 pm dose) and 2 h post-am dose for PK, hematology, and clinical chemistry analysis. All remaining animals were euthanized at 2 hrs post-dosing on Day 11 and blood samples were collected for PK, hematology, and clinical chemistry analysis. Data were analyzed using Graphpad prism software. Statistical analyses were performed using a one-way ANOVA with Dunnett s post-hoc test for group comparisons to ABT + vehicle treatment.