BMS986142 是一种有效的、具有高选择性的Bruton's 酪氨酸激酶 (BTK)可逆性抑制剂 (IC50:0.5 nM)。

Against a panel of 384 kinases, BMS-986142 is highly selective, with only five other kinases (Tec, ITK, BLK, Txk, BMX) inhibited with<100-fold selectivity for BTK. Four of these kinases are Tec family kinases, of which BTK is a member, and only Tec (IC50: 10 nM) is inhibited with<30-fold selectivity compared with BTK. BMS-986142 does not inhibit CD40L-induced expression of CD86 or CD69 on peripheral blood B cells (IC50>10,000 nM for both). When Ramos B cells are treated with anti-IgM to activate BCR, BMS-986142 inhibits BTK-dependent calcium flux (IC50: 9 nM) [2].

BMS-986142 is a potent and highly selective reversible BTK inhibitor (IC50: 0.5 nM).

Against a panel of 384 kinases, BMS-986142 is highly selective, with only five other kinases (Tec, ITK, BLK, Txk, BMX) inhibited with<100-fold selectivity for btk. four of these kinases are tec family kinases, which btk is a member, and only (ic50: 10 nm) inhibited with<30-fold compared bms-986142 does not inhibit cd40l-induced expression cd86 or cd69 on peripheral blood b cells (ic50>10,000 nM for both). When Ramos B cells are treated with anti-IgM to activate BCR, BMS-986142 inhibits BTK-dependent calcium flux (IC50: 9 nM) [2].

BMS-986142 at 4, 10, and 30 mg/kg results in dose-dependent reductions of 26%, 43%, and 79% in clinically evident disease, respectively. Interestingly, 4 mg/kg BMS-986142 provides an additive benefit in clinical scores (54% inhibition) when co-administered with MTX versus 19% inhibition with MTX alone. Co-administration of BMS-986142 at 4 mg/kg with MTX result in a 53% reduction in inflammation and bone resorption compared with 24% and 10%, respectively, with either drug alone. Furthermore, serum anti-collagen II IgG titers are significantly inhibited with 10 and 30 mg/kg BMS-986142. BMS-986142 also produces dose-dependent reductions in clinical scores when the administration is delayed until the collagen booster on day 21. BMS-986142 doses of 2, 4, and 25 mg/kg in this therapeutic dosing regimen result in clinical score reductions of 17%, 37%, and 67%, respectively, at the end of the study [2].

Male DBA/1 mice are injected subcutaneously at the base of the tail with bovine type II collagen (200 μg) admixed. The mice are boosted 21 days later in the same manner. For preventative administration, PO QD dosing is immediately started with BMS-986142 in EtOH: TPGS: PEG300 (5:5:90); for therapeutic administration, the start of dosing is delayed until the booster immunization on day 21. For BMS-986142 plus MTX preventative studies, mice receive vehicle; BMS-986142 at 4, 10, or 30 mg/kg; BMS-986142 at 4 mg/kg plus MTX 0.25 mg/kg; or MTX at 0.25 mg/kg daily. For BMS-986142 plus etanercept therapeutic studies, mice receive vehicle daily; BMS-986142 at 2, 4, or 25 mg/kg daily; BMS-986142 at 2 or 4 mg/kg daily plus etanercept at 15 mg/kg IP twice weekly (BIW); or etanercept at 15 mg/kg IP BIW. For BMS-986142 plus murine cytotoxic T lymphocyte-associated protein 4 immunoglobulins (CTLA-4-Ig) preventative studies, mice receive vehicle daily; BMS-986142 at 10 or 30 mg/kg daily; murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW; or BMS-986142 at 10 mg/kg daily plus murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW. Dosing proceeds from day 0 through study completion (36 days).

1643368-58-4

C32H30F2N4O4

572.613

DMSO:120 mg/mL
H2O:Insoluble
Powder: -20°C for 3 years
In solvent: -80°C for 2 years