Alpha-1 Antitrypsin Modulators for Liver and Lung Disease
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Solution Overview
Problem
Current treatments for alpha-1 antitrypsin deficiency (AATD) are inadequate, as augmentation therapy does not fully restore normal physiological regulation of AAT and cannot address liver disease driven by the toxic gain-of-function of the Z allele, and existing therapies require frequent infusions and have limited efficacy during active lung infections.
Innovation Solution
Development of compounds, such as those represented by Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), which modulate AAT activity, offering potential therapeutic benefits for AATD by administering these compounds or their tautomers, deuterated derivatives, and pharmaceutically acceptable salts to patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If augmentation therapy is administered to increase circulating AAT levels, then lung protection is improved, but liver disease cannot be addressed and normal physiological regulation is not restored
Solution Approach 1:
The patent uses small molecule compounds as intermediaries that bind to AAT and modulate its conformational equilibrium. These compounds act as mediators between the Z-AAT mutant protein and its functional state, shifting the equilibrium toward the R-state (relaxed, active conformation) without requiring exogenous AAT infusion. This allows the body's own AAT production to be enhanced in function while potentially addressing liver pathology.
Solution Approach 2:
The invention changes the conformational parameters of AAT by introducing allosteric modulators that shift the protein's equilibrium between T-state (tense, inactive) and R-state (relaxed, active). This parameter change in protein conformation enhances the activity of endogenous AAT, particularly in PiZZ individuals, without requiring external protein replacement.
2Duration of action of stationary object
If augmentation therapy is administered weekly, then some disease progression is slowed, but treatment burden increases and efficacy is limited during active infections
Solution Approach 1:
The patent enables the body's own AAT production system to serve itself by enhancing the function of endogenous AAT through small molecule modulators. Instead of requiring external weekly infusions, the treatment activates the patient's own AAT pool, allowing continuous protection without repeated medical interventions. The compounds orally or via other routes can be administered less frequently.
Solution Approach 2:
The invention transitions from periodic weekly infusions to potentially less frequent administration of small molecule compounds that sustain AAT modulation over extended periods. The pharmacokinetics of these compounds can provide continuous effect, reducing the periodic treatment burden while maintaining protection during active infections.
3Quantity of substance
If Z-AAT protein is produced in liver cells, then circulating AAT levels are reduced due to misfolding, but polymerization within cells causes cytotoxicity and liver disease
Solution Approach 1:
The patent applies preliminary action by using small molecule compounds to prevent the misfolding and polymerization of Z-AAT before it can accumulate in the endoplasmic reticulum and cause cytotoxicity. The modulators bind to Z-AAT and stabilize its folded conformation, preventing the harmful polymerization process from initiating in the first place.
Solution Approach 2:
The invention converts the harmful Z-AAT mutant protein into a beneficial protective agent by using small molecule modulators to shift its conformational equilibrium toward the active R-state. The same Z-AAT that would normally polymerize and cause liver disease is instead stabilized in a functional conformation that can circulate and protect the lungs, effectively converting the harmful mutant into a protective factor.
Data Source
AI summary
Novel compounds, compositions, and methods of using and preparing the same, which maybe useful for treating alpha-1 antitrypsin deficiency (AATD).