Reducing hERG Inhibition in the Design of Potent and Bioavailable Indazole cGAS Inhibitors

Area of Science:

• Immunology
• Medicinal Chemistry
• Pharmacology

Background:

• Cyclic GMP-AMP synthase (cGAS) is crucial in the innate immune response to pathogens via the cGAS-STING pathway.
• cGAS activation leads to increased pro-inflammatory mediators, making cGAS inhibition a therapeutic target for autoimmune and neurodegenerative diseases.

Purpose of the Study:

• To optimize tetrahydrocarboline cGAS inhibitor 3 for therapeutic use.
• To mitigate hERG channel activity and enhance bioavailability of cGAS inhibitors.
• To identify a potent cGAS inhibitor with favorable pharmacokinetic properties.

Main Methods:

• Medicinal chemistry optimization of tetrahydrocarboline scaffold.
• Systematic modification to control compound polarity.
• In vitro assays for permeability, stability, and hERG activity.
• In vivo pharmacokinetic studies in mice.

Main Results:

• Meticulous control of polarity was essential for improving in vitro ADME (absorption, distribution, metabolism, excretion) properties.
• Optimization efforts successfully mitigated off-target hERG channel activity.
• Compound 26 emerged as a potent cGAS inhibitor.
• Compound 26 demonstrated favorable pharmacokinetic parameters in mouse models.

Conclusions:

• Optimized tetrahydrocarboline derivatives can serve as effective cGAS inhibitors.
• Compound 26 represents a promising drug candidate for conditions involving aberrant cGAS-STING pathway activation.
• Balancing potency, safety (hERG activity), and pharmacokinetics is critical for developing therapeutic cGAS inhibitors.