Ferrostatin Derivatives With Solubility and Plasma Availability
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Solution Overview
Problem
There is a need for small molecules that effectively inhibit ferroptosis and/or oxytosis, with high selectivity, solubility, and improved pharmacokinetic profiles for the treatment of associated diseases.
Innovation Solution
Development of ferrostatin-1 derivative compounds with specific structural modifications that exhibit potent inhibitory activity against ferroptosis and oxytosis, showing excellent solubility, radical-trapping ability, and high human microsomal stability, suitable for parenteral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If iron chelators and metal protein-attenuating compounds are used to block iron-dependent cell death, then neuronal cell death is inhibited, but solubility and pharmacokinetic properties are insufficient for therapeutic use
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of ferrostatin-1 derivatives, specifically changing the aromatic ring substitutions, alkyl chain lengths, and functional groups to optimize both inhibitory activity and solubility parameters for therapeutic use
Solution Approach 2:
The patent creates composite molecular structures by combining the core ferrostatin-1 scaffold with various substituent groups (aryl, heteroaryl, cycloalkyl, alkyl chains) to produce derivative compounds that integrate multiple functional properties including enhanced solubility, radical-trapping ability, and ferroptosis inhibition
2Measurement precision
If small molecules are designed to inhibit ferroptosis with high selectivity, then anti-ferroptotic activity increases, but pharmacokinetic profiles and plasma availability are insufficient
Solution Approach 1:
The patent applies local quality by introducing specific functional groups at particular positions on the molecular scaffold (such as hydroxyl groups, alkoxy chains, and aromatic substitutions) to locally enhance solubility and pharmacokinetic properties without compromising the core inhibitory mechanism
Solution Approach 2:
The patent employs dynamics by creating a series of derivative compounds with varying structural flexibility and conformational properties, allowing optimization of plasma availability and pharmacokinetic profiles while maintaining high selectivity for ferroptosis inhibition
3Ease of operation
If ferrostatin-1 derivatives are developed for parenteral administration, then plasma availability improves, but manufacturing complexity increases
Solution Approach 1:
The patent develops small molecule derivatives that can be administered as single-dose or short-course therapies, reducing the need for complex long-term manufacturing and storage infrastructure while achieving therapeutic plasma availability
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These compounds demonstrate potent in vitro anti-ferroptotic activity in the low nanomolar range and good plasma availability, making them suitable for therapeutic use in treating diseases associated with ferroptosis and oxytosis.
Implementation Method 1
they show very potent in vitro anti-ferroptotic activity in the low nanomolar range, good radical-trapping ability
Implementation Method 2
Cell membrane rupture during ferroptotic cell death is characterized by hydrogen abstraction and oxygenation of poly unsaturated fatty acids (PUFAs) of phospholipids (PLs), which is catalysed by redox-active iron
Implementation Method 3
glutamine- and oxidative stress induced cell death are inhibited by iron chelation
Data Source
AI summary
The present invention relates to a compound of formula (I) or a stereoisomer, or tautomer, wherein moiety A, R1, and R2 have the same meaning as that defined in the claims and the description. The present invention also relates to the use of such compounds for the prevention and/or treatment of a disease associated with ferroptosis and/or oxytosis such as liver disease, chronic kidney disease, lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, prevention of transplant rejection, iron toxicity, iron metabolism-related disease and genetic disorder of GPX4. The present invention also provides pharmaceutical compositions comprising such compounds, as well as the use of the compounds as a medicament and methods of prevention and/or treatment of such diseases.