Novel substituted pyrimidines as HCV replication (replicase) inhibitors

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• Hepatitis C virus (HCV) remains a significant global health concern.
• Development of effective antiviral therapies is crucial for HCV eradication.
• Early-stage research identified Compound 1 as an initial HCV replication inhibitor.

Purpose of the Study:

• To improve the potency and safety profile of HCV replication inhibitors.
• To explore structural modifications of the 5-azo linkage in identified compounds.
• To identify novel carbanucleoside-like derivatives with enhanced anti-HCV activity.

Main Methods:

• Structure-Activity Relationship (SAR) studies focused on the 5-azo linkage.
• Replacement of the 5-azo moiety with 5-alkenyl and 5-alkynyl groups.
• Evaluation of compound potency against HCV replicons, selectivity, and in vivo characteristics.
• Initial target engagement studies to elucidate the mechanism of action.

Main Results:

• Modulation of the 5-azo linkage led to initial potency improvements.
• Replacement of the 5-azo linkage with 5-alkynyl moieties yielded potent HCV replication inhibitors.
• Compounds 53 and 63 demonstrated favorable replicon potency, selectivity, and in vivo profiles.
• Novel carbanucleoside-like derivatives were identified as potential inhibitors of the HCV replication complex.

Conclusions:

• The 5-alkynyl linkage is a promising modification for developing potent HCV inhibitors.
• Compounds 53 and 63 represent advanced drug candidates with a good overall profile.
• These novel derivatives may exert their antiviral effect by inhibiting the HCV replicase complex.