Indole Derivative Compounds for Selective HIV Splicing Inhibition
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Solution Overview
Problem
Current strategies for correcting abnormal splicing defects, such as those causing AIDS, are costly and require the use of expensive molecules like antisense oligonucleotides and PNA, and often involve expression vectors, while existing indole derivatives used for treating splicing-related diseases can cause cellular toxicity due to their flat structure intercalating with DNA.
Innovation Solution
Development of novel indole derivative compounds with a specific structural formula that selectively inhibit splicing events with reduced cellular toxicity, minimizing DNA intercalation risks and using them for treating AIDS.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If indole derivative compounds with flat structure are used to treat splicing-related diseases, then therapeutic effect is achieved, but cellular toxicity increases due to DNA intercalation
Solution Approach 1:
The patent modifies the molecular structure parameters of indole derivatives by introducing specific substituents (halogens, alkyl groups, alkoxy groups) at defined positions, changing the physical and chemical properties to reduce DNA intercalation while preserving splicing correction activity
Solution Approach 2:
The invention applies different functional groups at specific locations on the indole core structure (positions 1, 2, 3, 4, 5, 6, 7, 8) to create localized modifications that reduce toxicity in certain regions while maintaining therapeutic activity in other regions
2Reliability
If antisense oligonucleotides and PNA are used to correct splicing defects, then splicing correction is achieved, but treatment cost increases
Solution Approach 1:
The patent employs small molecule indole derivatives that can be synthesized through conventional organic chemistry methods, replacing expensive oligonucleotide-based therapies with more cost-effective small molecule compounds that achieve similar splicing correction effects
3Productivity
If existing anti-retroviral compounds are used to inhibit viral replication, then viral load reduction is achieved, but they cannot address splicing defects in HIV
Solution Approach 1:
The patent develops indole derivative compounds that possess dual functionality: they can correct splicing defects in HIV viral RNA and simultaneously inhibit viral replication, making them more versatile than conventional anti-retrovirals that target only replication enzymes
Data Source
AI summary
The present invention relates to compound (I) for use as an agent for preventing, inhibiting or treating AIDS. The present invention further relates to compounds of formula (I) wherein X is CR0 or N; R0, R1, R2, R3, R4, R7 and R8 independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C5)alkyl group, a (C3-C6)cycloalkyl group, a (C1-C5)fluoroalkyl group, a (C1-C5)alkoxy group, a (C1-C5)fluoroalkoxy group, a -CN group, a -COORa group, a -NO2 group, a -NRaRb group, a -NRa-SO2-NRaRb group, a -NRaSO2Ra group, a -NRa-C(=0)-Ra group, a -NRa-C(=0)-NRaRb group, a -SO2-NRaRb group, a -SO3H group, a -OH group, a -O-SO2-ORc group, a -O-P(=O)-(ORc)(ORd) group, a -O-CH2-COORc group and can further be a group chosen among: (IIa), (IIIa), R5 represents a hydrogen atom, a (CrC5)alkyl group or a (C3-C6)cycloalkyl group; R10 is a hydrogen atom or a chlorine atom, and R11 is a hydrogen atom or a (C1-C4)alkyl group or anyone of its pharmaceutically acceptable salts.