Metabolically Stable AT2 Agonist Compounds for ILDs
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Solution Overview
Problem
Current treatments for interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF), are limited in efficacy and safety, with existing drugs causing side effects and lacking the ability to effectively slow or reverse the progression of the disease, and there is a need for safer and more effective therapeutic approaches.
Innovation Solution
Development of chemically-modified compounds that act as selective angiotensin II type 2 (AT2) receptor agonists with improved metabolic stability and reduced CYP enzyme inhibition, offering potential therapeutic benefits for ILDs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing drugs are used to treat interstitial lung diseases, then treatment is provided, but the drugs cause side effects and lack efficacy in slowing or reversing disease progression
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of AT2 receptor agonists through various substitutions (R1-R6 groups, Y1-Y4 linkers) to optimize both efficacy and safety profiles. The compounds of formula I represent systematic variations of the core structure to achieve improved therapeutic index
Solution Approach 2:
The patent employs local quality by introducing specific functional groups at different positions of the molecular structure (R1 at position 1, R2/R3 at position 3, R4 at position 4, etc.) to enhance specific pharmacological properties while minimizing off-target effects and side effects
2Productivity
If current therapies are administered, then some treatment effect is achieved, but the ability to slow or reverse disease progression is insufficient
Solution Approach 1:
The patent employs preliminary action by developing compounds with enhanced metabolic stability that can maintain therapeutic effects over extended periods, thereby proactively controlling disease progression rather than merely responding to symptoms
Solution Approach 2:
The patent achieves continuity of useful action through compounds designed for sustained receptor activation and improved pharmacokinetic properties, ensuring continuous therapeutic effect to progressively slow or reverse fibrotic changes in the lungs
3Reliability
If chemically-modified AT2 receptor agonists are developed, then potency and stability are improved, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the molecule into distinct functional modules: a core structure (positions 1, 3, 4, 5) and variable substituent groups (R1-R6, Y1-Y4). This modular approach allows systematic optimization of stability without completely redesigning the entire molecule
Solution Approach 2:
The patent employs universality by designing a core structural framework that maintains AT2 receptor agonist activity while allowing various substituent combinations. The core structure serves multiple functions (receptor binding, metabolic stability) while substituents provide tunable properties
Data Source
AI summary
There is provided herein a compound of formula I, wherein R1, R2, R3 Y1, Y2, Y3, Y4, R4, R5 and R6 are as defined herein, which compounds are useful in the treatment of autoimmune and/or fibrotic diseases, including interstitial lung diseases, such as idiopathic pulmonary fibrosis and sarcoidosis.