Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Structural Biology

Background:

• Retinoid-related orphan receptor gamma t (RORγt) is a key regulator of immune responses and a therapeutic target for autoimmune diseases.
• Previous structure-activity relationship (SAR) studies identified BMS-986251 as a clinical RORγt inverse agonist.

Purpose of the Study:

• To discover novel RORγt inverse agonists with structural features distinct from BMS-986251.
• To characterize the structure-activity relationship and preclinical efficacy of newly identified analogues.

Main Methods:

• Synthesis and characterization of tricyclic-carbocyclic RORγt inverse agonist analogues.
• X-ray co-crystallography to determine the binding mode of compound 3d with the RORγt ligand binding domain.
• In vitro and in vivo pharmacokinetic profiling of compound 3d.
• Evaluation of compound 3d efficacy in preclinical models of psoriasis (IMQ-induced skin lesion and IL-23-induced acanthosis models).

Main Results:

• Identification of novel RORγt inverse agonists, including compound 3d (BMS-986313), structurally different from BMS-986251.
• X-ray crystallography revealed distinct binding interactions of compound 3d within the RORγt ligand binding domain compared to BMS-986251.
• Compound 3d exhibited favorable in vitro and in vivo pharmacokinetic profiles.
• Compound 3d demonstrated robust efficacy in two preclinical psoriasis models, comparable to BMS-986251.

Conclusions:

• Novel RORγt inverse agonists with distinct structural features and binding modes were successfully identified.
• Compound 3d represents a promising preclinical candidate for psoriasis treatment, demonstrating potent efficacy and favorable pharmacokinetics.
• These findings expand the chemical space for RORγt inverse agonists and provide a foundation for further drug development.