LOX Inhibitor Compounds Selective Enzyme Binding
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Solution Overview
Problem
Current LOX inhibitors are either non-selective, lack potency, or are unsuitable for clinical use, with only limited compounds having progressed to clinical trials, and none have been used clinically since 1978, highlighting a need for new and effective LOX inhibitors.
Innovation Solution
Development of specific compounds of formula I, or their pharmaceutically acceptable salts, which are designed to inhibit lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) enzymes, targeting conditions such as cancer, fibrotic diseases, and cardiovascular conditions, with a focus on selectivity and improved potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing LOX inhibitors are used, then LOX activity is inhibited, but selectivity is poor and potency is insufficient
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific molecular structures (formula I) that target particular regions of the LOX enzyme active site. The compounds feature specific substituent patterns on the core structure that selectively interact with conserved residues in the catalytic domain, achieving high selectivity for LOX over other enzymes while maintaining potent inhibition.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters of the inhibitor structure, including substituent types, positions, and steric properties. This structural optimization allows fine-tuning of binding affinity and selectivity, transforming early-generation non-selective inhibitors into highly specific compounds with improved therapeutic potential.
2Reliability
If existing LOX inhibitors are used, then LOX activity is inhibited, but clinical suitability is compromised
Solution Approach 1:
The patent applies this principle by developing a series of compounds with optimized pharmacological properties that replace outdated inhibitors. The new compounds (formula I) are designed with improved metabolic stability and pharmacokinetic profiles, making them suitable for clinical development unlike previous generation inhibitors that were ineffective or toxic.
Solution Approach 2:
The patent uses parameter changes to optimize compounds for clinical use by adjusting molecular weight, lipophilicity, and other pharmacokinetic parameters. The structural modifications in formula I compounds improve bioavailability and reduce off-target effects, transforming laboratory inhibitors into clinically viable candidates.
3Reliability
If non-selective LOX inhibitors are used, then LOX activity is inhibited, but off-target effects increase
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific molecular structures (formula I) that target particular regions of the LOX enzyme active site. The compounds feature specific substituent patterns on the core structure that selectively interact with conserved residues in the catalytic domain, achieving high selectivity for LOX over other enzymes while maintaining potent inhibition.
Solution Approach 2:
The patent converts the potential harm of non-selective inhibition into benefit by using structure-activity relationship analysis to identify selective binding modes. The compounds are designed to exploit specific structural features of LOX that are absent in other enzymes, transforming what could be non-selective binding into highly specific enzyme inhibition with favorable safety profiles.
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
The compounds effectively inhibit LOX and LOXL enzymes, offering potential therapeutic benefits for various conditions including cancer, fibrosis, and cardiovascular diseases, with improved selectivity and potency compared to existing inhibitors.
Implementation Method 1
compounds useful as lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family members (LOXL1, LOXL2, LOXL3, LOXL4) inhibitors
Implementation Method 2
LOX (protein-6-lysine-oxidase; EC 1.4.3.13) is an extracellular enzyme that catalyses oxidative deamination of the primary amines of lysine and hydroxylysine in proteins
Data Source
AI summary
This invention relates to compounds useful as lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family member (LOXL1, LOXL2, LOXL3, LOXL4) inhibitors. In addition there are contemplated pharmaceutical compositions comprising the compounds and the use of the compounds in the treatment of conditions mediated by LOX and LOXL, for example cancer. In particular a LOX inhibitor such as the present compounds may be for use in the treatment of a cancer associated with EGFR. The present invention also contemplates the identification of biomarkers that predict responsiveness to a LOX inhibitor.