Pyrazolo-Pyridone Modulators for DCN1 N-Acetyl Pocket Binding
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Solution Overview
Problem
Current DCN1 inhibitors, such as N-benzyl piperidines, face limitations in accessing the N-acetyl pocket of DCN1, lack 3-dimensional character, and have a moderate murine half-life requiring frequent dosing, necessitating the development of more effective DCN1 inhibitors.
Innovation Solution
Development of pharmaceutically active pyrazolo-pyridone modulators that target the DCN1/2-mediated cullin neddylation pathway, specifically compounds according to Formulas I and II, which enhance binding to the N-acetyl pocket and improve oral bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If N-benzyl piperidine inhibitors are used to target DCN1, then DCN1 activity is inhibited, but the inhibitors lack 3-dimensional character and cannot effectively access the N-acetyl pocket
Solution Approach 1:
The patent transitions from planar N-benzyl piperidine structures to three-dimensional pyrazolo-pyridone frameworks with axial chirality. This dimensional change enables the molecules to access the N-acetyl pocket of DCN1, which requires 3D structural character for effective binding. The chiral axis creates a three-dimensional arrangement that allows interaction with the pocket while maintaining inhibitory activity.
Solution Approach 2:
The pyrazolo-pyridone core introduces asymmetry through its fused five-membered pyrazole ring and six-membered pyridone ring system. This asymmetric structure creates a chiral axis that enables selective binding to the N-acetyl pocket, distinguishing it from the symmetric N-benzyl piperidine approach and improving inhibition effectiveness.
2Reliability
If N-benzyl piperidine inhibitors are used, then DCN1 activity is reduced, but the murine half-life is moderate requiring frequent dosing
Solution Approach 1:
The patent modifies key parameters of the inhibitor structure by incorporating the pyrazolo-pyridone core with specific substituents (R1-R7 groups). These structural parameter changes result in improved pharmacokinetic properties, including extended murine half-life and enhanced oral bioavailability, while maintaining DCN1 inhibitory activity.
3Reliability
If pyrazolo-pyridone modulators are developed to enhance binding to the N-acetyl pocket, then potency is improved, but the structural complexity increases
Solution Approach 1:
The patent merges the pyrazole and pyridone rings into a fused pyrazolo-pyridone core structure. This consolidation combines the binding characteristics of both ring systems into a single integrated framework that enhances affinity for the N-acetyl pocket while managing structural complexity through a unified molecular architecture.
Data Source
AI summary
A DCN1/2-mediated cullin neddylation modulator; a method for treating disorders associated with dysfunctional DCN1 and/or UBC12, Alzheimer's disease, other neurodegenerative diseases, bacterial infections, or viral infections; and a method for treating cancers are provided. The DCN1/2-mediated cullin neddylation modulator includes a compound according to Formula I disclosed herein. The methods include administering to a mammal a therapeutically effective amount of a compound according to Formula I. Also provided herein is a pharmaceutical composition including a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.