HDAC Inhibitor Composition for Selective HIV Latency Reversal

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Solution Overview

Problem

Current HDAC inhibitors used in treating HIV infection are not selective and cause adverse effects, making them unsuitable for individuals on combination antiretroviral therapy, while latently infected cells pose a challenge for viral rebound upon treatment cessation.

Innovation Solution

Development of novel, subtype-selective histone deacetylase inhibitors, represented by Compounds of Formula I, to activate HIV latency and potentially cure the infection alone or in combination with cART.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If non-selective HDAC inhibitors are used to activate latent HIV production, then viral activation from latently infected cells is achieved, but adverse effects occur making them unsuitable for patients on cART

Engineering Contradiction:

Improveefficacy in activating latent HIVVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing HDAC inhibitors with specific molecular structures that target particular HDAC isoforms (such as HDAC1, HDAC3, or HDAC11) rather than all HDAC enzymes indiscriminately. This selective binding to specific isoforms allows activation of latent HIV in infected cells while sparing healthy cells that rely on other HDAC isoforms for normal function, thereby reducing adverse effects while maintaining therapeutic efficacy

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying key molecular parameters of HDAC inhibitors including their chemical structure, binding affinity, and selectivity profile for different HDAC isoforms. By optimizing these parameters, the invention achieves compounds that effectively activate latent HIV production in latently infected cells while minimizing toxicity and adverse effects, making them suitable for use in patients on combination antiretroviral therapy

Inventive Principle:

Principle #35Parameter changes

2Reliability

If HDAC inhibitors are used to eliminate latently infected CD4+ T cells, then viral production is activated to kill infected cells, but poor selectivity leads to similar adverse effects across all HDAC inhibitor classes

Engineering Contradiction:

Improveability to eliminate latently infected cellsVSAvoidselectivity for specific HDAC subtypes

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies segmentation by dividing the HDAC enzyme family into distinct isoform categories (class I: HDAC1-3, 8; class IIa: HDAC4-7, 9; class IIb: HDAC10-11) and designing inhibitors that selectively target specific segments or isoforms. This segmentation approach allows the invention to achieve subtype-selective inhibition, enabling targeted activation of latent HIV in infected cells while preserving the function of other HDAC isoforms in healthy cells, thereby improving therapeutic index and reducing adverse effects

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP3941457B1Inhibitors of histone deacetylase useful for the treatment or prevention of HIV infection

Publication Date: 2026.01.21 MERCK SHARP & DOHME LLC

AI summary

The present invention relates to Compounds of Formula I and Ia and pharmaceutically acceptable salts or prodrug thereof, wherein R1, R2, X, A and B are as defined herein. The present invention also relates to compositions comprising at least one compound of Formula I or Ia, and methods of using the compounds of Formula I or Ia for treating or preventing HIV infection in a subject.