Tricyclic Compounds Inhibiting cccDNA for Hepatitis B Cure
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Solution Overview
Problem
Current treatments for chronic hepatitis B, particularly those targeting covalently closed circular DNA (cccDNA), fail to effectively eliminate or permanently silence cccDNA, which is crucial for achieving a complete cure as cccDNA persists and serves as a template for viral replication, leading to ongoing infection and liver complications.
Innovation Solution
Development of novel tricyclic compounds with specific structural features, such as those described in formula (I), which act as cccDNA inhibitors, demonstrating superior anti-HBV activity and favorable pharmacokinetic profiles, potentially capable of inhibiting or silencing cccDNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutics (interferons and nucleos(t)ide analogues) are used to treat chronic hepatitis B, then viral load is reduced and liver function improves, but cccDNA cannot be eliminated or permanently silenced
Solution Approach 1:
The patent employs parameter changes by developing compounds with specific molecular structures (formula I) that differ from existing therapeutics. These compounds feature modified chemical parameters including specific R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40 groups that enable permanent silencing of cccDNA, representing a fundamental change in therapeutic mechanism and chemical parameters compared to existing drugs.
2Reliability
If interferon treatment is administered to achieve sustained virological response, then HBsAg loss occurs in a small percentage of patients, but severe side effects are experienced
Solution Approach 1:
The patent applies parameter changes by developing novel compounds with specific molecular structures (formula I) that offer an alternative mechanism of action. These compounds feature modified chemical parameters including specific substituents at positions R1 through R40, enabling therapeutic effect through cccDNA silencing rather than immune modulation, thereby potentially achieving sustained response with reduced side effects.
3Reliability
If nucleos(t)ide analogues are used for long-term treatment, then viral load is profoundly reduced, but treatment must be continued indefinitely
Solution Approach 1:
The patent employs parameter changes by developing compounds with specific molecular structures (formula I) that target cccDNA permanently. These compounds feature modified chemical parameters including specific R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40 groups that enable permanent silencing of cccDNA, potentially allowing for finite treatment duration unlike indefinite NA therapy.
Data Source
AI summary
The present application provides compounds having the general formula: formula (I), wherein R1, R 2, A, X and m are as described herein, compositions including the compounds and methods of using the compounds. The compounds are useful as inhibitors of cccDNA for treating Hepatitis B Virus (HBV) infections.