HIV-1 CA-Targeting Compounds with CYP3A Inhibitors

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Solution Overview

Problem

Current CA-targeting antiviral drugs, such as PF-74, face challenges due to poor metabolic stability, particularly with CYP3A-mediated phase I metabolism, limiting their effectiveness as viable drug candidates for HIV treatment.

Innovation Solution

Development of potent HIV-1 CA-targeting molecules, specifically compounds of formulas I, II, and III, along with a pharmaceutical composition that includes a CYP3A inhibitor like Cobicistat, to enhance metabolic stability and antiviral efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If PF-74 is used as a CA-targeting antiviral drug, then potent antiviral activity is achieved, but metabolic stability is prohibitively poor

Engineering Contradiction:

Improveantiviral activityVSAvoidmetabolic stability

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of PF-74 through systematic variation of substituents at multiple positions (R1-R10 groups) to optimize the balance between antiviral activity and metabolic stability. This involves changing physical and chemical parameters of the molecule to reduce susceptibility to CYP3A-mediated metabolism while maintaining binding affinity to the CA-CA interface

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite molecular structures by combining the core PF-74 scaffold with various substituent groups (aromatic rings, heterocycles, alkyl chains) to generate a library of analogues. These composite structures aim to achieve both potent antiviral activity and improved metabolic stability by strategically placing metabolic stability-enhancing groups while maintaining the essential pharmacophore for CA binding

Inventive Principle:

Principle #40Composite materials

2Duration of action of stationary object

If metabolic stability is improved through structural modification, then drug viability is enhanced, but antiviral potency may be reduced

Engineering Contradiction:

Improvemetabolic stabilityVSAvoidantiviral activity

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The patent applies local quality by making targeted modifications at specific positions of the molecule (R1, R3, R4, R7, R10 positions) rather than global structural changes. Each substituent position is optimized independently to enhance metabolic stability at that local region while preserving the overall molecular architecture required for antiviral activity at the CA-CA interface

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs partial action by introducing substituent groups that provide moderate metabolic stability enhancement without completely transforming the core structure. This allows retention of sufficient antiviral potency while achieving the necessary improvement in metabolic stability to reach drug viability thresholds

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS11850247B2Antiviral compounds

Publication Date: 2023.12.26 REGENTS OF THE UNIVERSITY OF MINNESOTA

AI summary

The invention provides a compound of formula I, formula II, or formula III:or a salt thereof, wherein R1-R10 have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful as HIV-1 CA-targeting molecules and as antiviral agents.