Reversible DPP1 Inhibitors for Selective Neutrophil Elastase Control
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Solution Overview
Problem
There is a need for novel DPP1 inhibitors to treat diseases associated with DPP1 and neutrophil elastase, such as hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemic-reperfusion injury, and rheumatoid arthritis, as unregulated neutrophil elastase can cause tissue destruction and inflammation.
Innovation Solution
Development of compounds of formula (I), (II), (III), (III-A), and (III-B) or their pharmaceutically acceptable salts or deuterated forms, which act as DPP1 inhibitors, potentially targeting DPP1 to regulate neutrophil elastase activity and mitigate its harmful effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If DPP1 is inhibited to reduce neutrophil elastase activity, then tissue destruction and inflammation are alleviated, but DPP1's normal physiological functions in lysosomal protein degradation and immune cell activation may be compromised
Solution Approach 1:
The patent employs reversible covalent inhibition through a warhead group that forms a dynamic, reversible bond with the catalytic cysteine residue of DPP1. This allows the inhibitor to bind and modulate DPP1 activity rather than permanently blocking it, enabling the enzyme to still perform its physiological functions when not bound to the inhibitor, thus resolving the contradiction between inhibiting harmful activity and maintaining normal function
Solution Approach 2:
The patent modifies the inhibitor structure to include an electrophilic warhead group that reacts with the nucleophilic catalytic cysteine residue, changing the chemical state of the enzyme-inhibitor interaction from non-covalent to covalent bonding. This parameter change in bond strength and reversibility allows for controlled modulation of DPP1 activity, achieving inhibition of harmful effects while preserving essential physiological functions
2Productivity
If strong inhibitors are used to effectively block neutrophil elastase activation, then therapeutic benefit is increased, but selectivity against other proteases may be reduced leading to off-target effects
Solution Approach 1:
The patent designs the inhibitor with distinct functional regions: an electrophilic warhead group that specifically targets the catalytic cysteine residue of DPP1, and a heterocyclic core structure that provides selectivity through specific spatial and electronic interactions with the DPP1 active site. This local differentiation of functional properties within the molecule enables both strong inhibition and protease selectivity
Solution Approach 2:
The patent uses the catalytic cysteine residue of DPP1 as an intermediary target, as this residue is unique to cysteine proteases like DPP1 and absent in serine proteases such as neutrophil elastase. By targeting this specific intermediary component rather than the protease activity directly, the inhibitor achieves high selectivity while maintaining potent inhibition of DPP1-mediated neutrophil elastase activation
Data Source
AI summary
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or deuterated forms thereof, wherein R0, L and R1 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, e.g., in the treatment of a disease that is treatable by administration of a DPP1 inhibitor.