Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cardiovascular Science

Background:

• CCR5 antagonists are crucial for HIV-1 treatment.
• hERG channel inhibition is a significant safety concern for drug candidates.
• Developing HIV-1 inhibitors with reduced cardiac side effects is a priority.

Purpose of the Study:

• To design and synthesize novel thiophene-3-yl-methyl ureas as CCR5 antagonists.
• To mitigate hERG channel inhibition liability in HIV-1 inhibitors.
• To investigate the impact of structural modifications on pharmacological activity and cardiac safety.

Main Methods:

• Design and synthesis of thiophene-3-yl-methyl urea analogs.
• Pharmacological evaluation for HIV-1 inhibition.
• Assessment of hERG channel inhibition using in vitro assays.
• Electrophysiological studies in dog Purkinje fibers to assess action potential duration (APD).

Main Results:

• A series of thiophene-3-yl-methyl ureas demonstrated potent HIV-1 inhibition.
• Reduced lipophilicity and subtle structural modifications successfully mitigated hERG inhibition.
• Compounds with low hERG inhibition exhibited prolonged APD in dog Purkinje fibers, indicating potential mixed cardiac ion channel effects.

Conclusions:

• Novel thiophene-3-yl-methyl ureas offer a promising scaffold for developing safe and effective HIV-1 CCR5 antagonists.
• Lipophilicity reduction is a key strategy for mitigating hERG liability, but careful structural design is essential.
• Further investigation into the mixed cardiac ion channel effects is warranted for these compounds.