Selective AT2 Agonist Compounds for Reduced CYP Inhibition
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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 having minimal impact on disease progression, and there is a need for more potent and stable angiotensin II type 2 (AT2) receptor agonists that minimize Cytochrome P450 enzyme inhibition.
Innovation Solution
Development of novel angiotensin II type 2 receptor agonists with improved metabolic stability and reduced CYP enzyme inhibition, represented by specific chemical compounds of formula I, which act as selective AT2 receptor agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing AT2 receptor agonists are used to treat interstitial lung diseases, then therapeutic effects are achieved, but CYP enzyme inhibition occurs causing side effects and reduced safety
Solution Approach 1:
The patent modifies chemical parameters of AT2 agonists by replacing the carboxylic acid group with bioisosteric groups (tetrazole, triazole, oxadiazole, thiadiazole rings) to reduce CYP enzyme inhibition while preserving AT2 receptor affinity and selectivity, thereby improving safety profile while maintaining therapeutic efficacy
Solution Approach 2:
The patent creates composite molecular structures combining AT2 agonist core structures with various bioisosteric replacements (different heterocyclic rings with varying electronic and steric properties) to optimize the balance between therapeutic efficacy and reduced CYP inhibition, allowing selection of compounds with improved safety profiles
2Reliability
If existing AT2 receptor agonists are used, then some therapeutic benefit is achieved, but metabolic stability is poor leading to rapid degradation
Solution Approach 1:
The patent changes the chemical structure parameters by replacing metabolically labile carboxylic acid groups with metabolically stable heterocyclic bioisosters, thereby improving metabolic stability and half-life while maintaining or enhancing AT2 receptor activity and therapeutic benefit
3Ease of operation
If current ILD treatments are used, then some symptomatic relief is provided, but efficacy is limited and side effects occur
Solution Approach 1:
The patent extracts and targets the specific AT2 receptor pathway responsible for beneficial effects in ILD while excluding AT1 receptor-mediated harmful effects through selective agonism, thereby improving therapeutic efficacy by selectively activating only the therapeutic pathway without the side effects of non-selective treatments
Data Source
AI summary
There is provided pharmaceutical compounds of formula I,wherein R1, R2, R3, R4, R5, R6, Y1, Y2, Y3, X and Z have meanings given in the description, which compounds are useful in the treatment of autoimmune and/or fibrotic diseases, including interstitial lung diseases, such as idiopathic pulmonary fibrosis and sarcoidosis.