Stereochemical Differences in Fluorocyclopropyl Amides Enable Tuning of Btk Inhibition and Off-Target Activity

Area of Science:

• Medicinal Chemistry
• Immunology
• Drug Discovery

Background:

• Bruton's tyrosine kinase (Btk) is implicated in autoimmune diseases like rheumatoid arthritis and lupus.
• Current irreversible Btk inhibitors are approved for hematologic cancers, not autoimmune conditions.

Purpose of the Study:

• To develop novel reversible Btk inhibitors for chronic immune diseases.
• To explore cyclopropyl amide isosteres to occupy the H2 pocket and improve upon existing inhibitors.

Main Methods:

• Design and synthesis of novel Btk inhibitors incorporating cyclopropyl amide isosteres.
• Evaluation of Btk inhibition, selectivity, and drug-like properties.
• Assessment of hERG channel inhibition as a safety parameter.
• Stereochemical analysis of fluorocyclopropyl amide derivatives.

Main Results:

• Novel reversible Btk inhibitors were synthesized, retaining or improving drug-like properties.
• A safety liability, hERG inhibition, was observed with some derivatives.
• Incorporation of a fluorocyclopropyl amide led to stereodependent Btk and off-target activity.
• The (R,R)-stereoisomer emerged as a lead compound with optimized properties.

Conclusions:

• Reversible Btk inhibitors with cyclopropyl amide isosteres represent a promising strategy for autoimmune diseases.
• Stereochemistry is critical for optimizing Btk inhibitor activity and mitigating off-target effects like hERG inhibition.
• The identified (R,R)-stereoisomer warrants further investigation as a potential therapeutic agent.