Bicyclic Ligand-Biased Agonists of S1P₁: Exploring Side Chain Modifications to Modulate the PK, PD, and Safety...

Area of Science:

• Medicinal Chemistry
• Immunology
• Pharmacology

Background:

• Sphingosine-1-phosphate (S1P) receptors are crucial in vascular and immune systems.
• S1P receptor modulators are investigated for autoimmune diseases due to lymphopenia induction.
• Previous S1P1 modulator BMS-986104 had a long half-life and limited metabolite formation.

Purpose of the Study:

• To optimize S1P1 modulators for better pharmacokinetics and metabolite formation.
• To discover potent and biased S1P1 agonists with improved safety and efficacy profiles.
• To evaluate new compounds in preclinical models of autoimmune disorders.

Main Methods:

• Chemical synthesis and structural modification of S1P1 modulators.
• In vitro and in vivo pharmacokinetic and pharmacodynamic assessments.
• Evaluation of compound efficacy in arthritis models.

Main Results:

• Compounds 12 and 24 are potent, biased S1P1 agonists.
• These new compounds exhibit shorter in vivo half-lives across species.
• Projected human half-lives are significantly reduced compared to previous candidates.
• Compounds 12 and 24 demonstrated robust efficacy in arthritis models.

Conclusions:

• Optimization of S1P1 modulators led to compounds with improved pharmacokinetic properties.
• Compounds 12 and 24 represent promising therapeutic candidates for autoimmune diseases.
• The developed compounds maintain efficacy and safety profiles while offering better drug-like properties.