BMS-986251

BMS-986251 is an orally active and selective RORγt inverse agonist with an EC50 of 12 nM for RORγt GAL4. BMS-986251 inhibits IL-17 with an EC50 of 24 nM in human whole blood assay. BMS-986251 demonstrates robust efficacy in mouse acanthosis and Imiquimod-induced models (preclinical models of psoriasis).

BMS-986251 is against ROR family members (RORα GAL4: EC₅₀>10 μM; RORβ GAL4: EC₅₀>10 μM) and against other nuclear receptors (PXR: EC₅₀>5 μM; LXRα: EC₅₀>7.5 μM; LXRβ: EC₅₀>7.5 μM). BMS-986251 does not inhibit any of the CYP’s^[1].

BMS-986251 (5-45 mg/kg; orally; twice daily until day 9) results in reduced ear thickness^[1].
BMS-986251 (0.13, 0.79, 4.76 mg/kg; orally; once a day) displays a dose-dependent reduction of the IL-17F produced in naïve C57BL/6 female mice (7-9 weeks)^[1].
BMS-986251 (2 mg/kg of IV and 4 mg/kg of PO) has a T_1/2 of 7.7 hours, a CL of 2.7 mL/min•kg, and a V_ss of 1.9 L/kg for IV in mouse^[1].

References:
[1]. Robert J. Cherney, et al. Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist. ACS Med. Chem. Lett. 2020, 11, 6, 1221–1227