Structure-Based Design of Potent TLR7/8/9 Triple Antagonists: Overcoming High Tissue Distribution and Reactive...

Area of Science:

• Immunology
• Medicinal Chemistry

Background:

• Endosomal Toll-like receptors (TLR) 7, 8, and 9 activation by self-nucleic acids drives autoimmune diseases such as systemic lupus erythematosus (SLE).
• Targeting these receptors offers a potential therapeutic strategy for autoimmune conditions.

Purpose of the Study:

• To discover and optimize novel, orally bioavailable small molecules acting as potent TLR7/8/9 triple antagonists.
• To develop drug candidates with improved pharmacokinetic properties and reduced liabilities for autoimmune disease treatment.

Main Methods:

• Design and synthesis of a novel series of "N-aryl-N" pharmacophore-containing compounds.
• Structure-guided optimization using TLR8 cocrystal structures and TLR7/9 homology models.
• Evaluation of potency, oral bioavailability, volume of distribution, and reactive metabolite liabilities in preclinical models.

Main Results:

• Discovery of a novel series of potent TLR7/8/9 triple antagonists.
• Optimization successfully balanced pan-TLR potency with drug-like properties, including reduced volume of distribution.
• Elimination of reactive metabolite liabilities and identification of lead compound 41.
• Compound 41 demonstrated robust, dose-dependent inhibition of TLR7 and TLR9 pathways in vivo.

Conclusions:

• The novel "N-aryl-N" series represents a promising class of TLR7/8/9 triple antagonists.
• Compound 41 exhibits favorable properties and preclinical efficacy, supporting its potential for treating autoimmune diseases.
• Targeting TLR7/8/9 offers a viable strategy for managing autoimmune conditions driven by self-nucleic acid activation.