Triazole P97 Inhibitors for Proteostatic Disorder Treatment
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Solution Overview
Problem
There is a need for inhibitors and modulators of the AAA ATPase p97 to treat cancer and neurodegenerative disorders caused by proteostatic malfunctions, with a requirement for compounds that are more efficacious and have fewer side effects than existing p97 inhibition mechanisms.
Innovation Solution
Development of specific compounds, such as those represented by Formulae (Ia), (Ib), (IIa), and (IIb), which are triazoles with p97 inhibitory or modulatory activity, administered to subjects to inhibit or modulate p97 activity, thereby treating conditions like inclusion body myopathy, Paget's disease of the bone, frontotemporal dementia, and amyotrophic lateral sclerosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing p97 inhibition mechanisms are used, then p97 activity is inhibited, but side effects increase and efficacy is reduced
Solution Approach 1:
The patent applies parameter changes by developing novel triazole compounds with specific molecular structures (Formulae Ia, Ib, IIa, IIb) that modify the inhibition mechanism of p97. These compounds feature specific substituents (R1-R9, Z, L, m, n) that tune the pharmacological parameters to achieve selective inhibition of p97 ATPase activity while minimizing off-target effects and side effects associated with existing inhibitors
Solution Approach 2:
The patent employs composite material principles by creating complex triazole-based molecular structures that combine multiple functional groups and substituents. The compounds integrate heterocyclic cores with various aromatic and aliphatic substituents to achieve optimal binding affinity and selectivity for p97, resulting in enhanced therapeutic efficacy and reduced side effects compared to simpler existing inhibitors
2Productivity
If p97 inhibition is increased to treat disease, then therapeutic benefit improves, but toxicity and side effects worsen
Solution Approach 1:
The patent applies local quality by designing triazole compounds with specific localized functional groups and substituents at different positions of the molecular core. The distinct substituents (R1-R9) provide localized interactions with specific residues in the p97 binding pocket, enabling selective inhibition that achieves therapeutic benefit while sparing other cellular processes from toxic effects
Solution Approach 2:
The patent uses intermediary principles by developing triazole compounds that act as selective mediators between the therapeutic goal (p97 inhibition) and cellular safety. These compounds serve as intermediate agents that bind to p97 with high selectivity, translating the desired therapeutic effect while filtering out toxic interactions with other cellular targets
Data Source
AI summary
The present technology is directed to methods of inhibiting or modulating p97 and compounds and compositions useful in such methods. Diseases and conditions that can be treated with the compounds and compositions of the present technology include, but are not limited to, antibacterial infection, antiviral infection, cancer and neurodegenerative disorders susceptible to treatment by modulation of p97.