Macrocyclic Antiviral Agents Inhibiting 3CLpro
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Solution Overview
Problem
Current therapies for coronavirus infections are inadequate, as existing compounds targeting the 3C-Like protease (3CLpro) have not been approved, and there is a high unmet clinical need for more effective treatments to inhibit coronavirus replication and prevent complications such as organ failure or death.
Innovation Solution
Development of novel antiviral compounds represented by Formula (I) and their pharmaceutical compositions that inhibit the 3C-Like protease, interfering with the coronavirus lifecycle, which are administered to mammals to treat or prevent coronavirus infections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds targeting 3CLpro are used, then some level of protease inhibition is achieved, but they have not been approved as coronavirus therapies due to inadequate effectiveness
Solution Approach 1:
The patent modifies the chemical structure parameters of existing 3CLpro inhibitor compounds by introducing specific macrocyclic frameworks and substituent groups (R1-R6, X, Y, Z, W) to enhance binding affinity and enzymatic inhibition potency, thereby improving therapeutic effectiveness to meet clinical approval standards
Solution Approach 2:
The invention creates composite molecular structures combining macrocyclic cores with various functional groups and side chains, forming complex inhibitor molecules that simultaneously achieve high protease binding affinity, appropriate pharmacokinetic properties, and safety profiles required for clinical approval
2Reliability
If more effective therapies are developed to inhibit coronavirus replication, then unmet clinical need is addressed, but complexity of compound structure increases
Solution Approach 1:
The inhibitor molecules are segmented into distinct functional regions: a macrocyclic core structure for primary binding, various substituent groups (R1-R6) for optimizing interactions with specific protease residues, and flexible linkers (X, Y, Z, W) for adapting to the enzyme active site geometry, allowing complex functionality to be organized into manageable structural modules
Solution Approach 2:
The macrocyclic framework serves multiple functions simultaneously: providing structural rigidity for precise positioning, offering multiple interaction points for binding to different residues in the protease active site, and enabling modulation of pharmacokinetic properties through substituent variation, thereby achieving high efficacy without proportionally increasing overall molecular complexity
Data Source
AI summary
The present invention discloses macrocyclic compounds of Formula (I), and pharmaceutically acceptable salts, thereof:which inhibit coronavirus replication activity. The invention further relates to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and methods of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.