Mtor Inhibitor Compounds Selective Atph Binding
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Solution Overview
Problem
Current mTOR inhibitors lack optimal selectivity and pharmacokinetic properties for effectively treating diseases associated with mTOR, often causing unwanted side effects due to non-specific kinase inhibition.
Innovation Solution
Development of novel compounds of formula (I) that selectively inhibit mTOR kinase activity by binding to the ATP-binding pocket, offering improved potency and specificity over other kinases like PI3K family members, thereby modulating cellular activities and treating diseases such as cancer and autoimmune disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current mTOR inhibitors are used to treat diseases, then mTOR kinase activity is inhibited, but selectivity is insufficient leading to non-specific kinase inhibition and unwanted side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (substituted phenyl or naphthyl groups combined with heterocyclic moieties) that target the ATP-binding pocket of mTOR with high selectivity. The molecular structure is optimized to fit the specific spatial and chemical characteristics of the mTOR binding site, distinguishing it from other kinase binding sites, thereby achieving selective inhibition without affecting other kinases.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as substituent types, ring structures, and molecular weight within the compound series. These parameter optimizations allow fine-tuning of the compounds' binding affinity and selectivity for mTOR, improving therapeutic efficacy while reducing off-target effects through precise molecular design.
2Reliability
If current mTOR inhibitors are used, then kinase activity is suppressed, but pharmacokinetic properties are suboptimal for effective treatment
Solution Approach 1:
The patent utilizes parameter changes by optimizing molecular weight, lipophilicity, and structural rigidity of the compounds. These parameter adjustments improve the compounds' absorption, distribution, metabolism, and excretion (ADME) properties, leading to better pharmacokinetic profiles and sustained therapeutic efficacy for treating diseases such as cancer and autoimmune disorders.
3Adaptability or versatility
If broad kinase inhibition is achieved, then multiple cellular pathways are affected, but specificity for mTOR pathways is reduced
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (substituted phenyl or naphthyl groups combined with heterocyclic moieties) that target the ATP-binding pocket of mTOR with high selectivity. The molecular structure is optimized to fit the specific spatial and chemical characteristics of the mTOR binding site, distinguishing it from other kinase binding sites, thereby achieving selective inhibition without affecting other kinases.
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 provide enhanced therapeutic efficacy with improved selectivity and pharmacokinetic properties, reducing side effects and effectively inhibiting mTOR pathways in diseases like cancer and autoimmune disorders, while also inducing autophagy for neurodegenerative disease management.
Implementation Method 1
selectively inhibit mTOR kinase activity by binding to the ATP-binding pocket
Implementation Method 2
inducing autophagy for neurodegenerative disease management
Data Source
AI summary
The invention relates to compounds of formula (I) wherein m, o, Ra, Rb, R1 and T1 have the meaning as cited in the description and the claims. Said compounds are useful as inhibitors of mTOR for the treatment or prophylaxis of mTOR related diseases and disorders. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the use as medicaments.