Bridgehead Azole SHP2 Inhibitors for BBB-Penetrant CNS Tumors
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing SHP2 inhibitors lack potency, selectivity, and pharmacokinetic properties, particularly in penetrating the blood-brain barrier (BBB) for treating CNS-related tumors.
Innovation Solution
Development of heterocyclic compounds with a specific azole ring, such as pyrazole or pyrrole, at the bridgehead, combined with a central heterocyclic core and substituents, to create potent and selective SHP2 inhibitors with improved ligand-biological target kinetics and BBB penetration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional heterocyclic scaffolds are used for SHP2 inhibition, then some level of inhibition is achieved, but potency and selectivity are insufficient
Solution Approach 1:
The patent modifies molecular parameters by introducing a five-membered fused azole ring (pyrazole or pyrrole) at the bridgehead position, changing the heterocyclic scaffold from conventional six-membered rings to this specific five-membered fused structure. This structural parameter change achieves low nanomolar or micromolar IC50 values for SHP2 inhibition, significantly improving potency and selectivity while maintaining manageable molecular complexity through the fused ring system.
2Quantity of substance
If SHP2 inhibitors are designed with standard pharmacokinetic properties, then oral administration is feasible, but plasma exposure and brain penetration are insufficient for CNS tumors
Solution Approach 1:
The patent optimizes pharmacokinetic parameters by incorporating the fused azole ring system, which improves plasma exposure (Cmax and AUC) after oral administration. The structural modification at the bridgehead position with the five-membered fused ring enhances bioavailability and plasma concentration, enabling effective treatment of CNS tumors while maintaining oral administrability.
Solution Approach 2:
The patent enables blood-brain barrier penetration by modifying the molecular structure to achieve appropriate lipophilicity and molecular size. The fused azole ring system provides a dimensional change in molecular properties that facilitates transport across the BBB, allowing the inhibitor to reach therapeutic concentrations in the CNS for treating brain tumors.
3Duration of action of moving object
If ligand-biological target kinetics are optimized, then residence time is extended, but synthesis complexity increases
Solution Approach 1:
The patent optimizes binding kinetics by introducing the fused azole ring system, which extends residence time by reducing the off-rate (koff). The specific five-membered fused heterocyclic structure at the bridgehead position creates enhanced interactions with the SHP2 target, prolonging the time the inhibitor remains bound. This kinetic optimization is achieved through a relatively straightforward synthesis approach from available starting materials.
Data Source
AI summary
The present invention relates to new compounds capable of inhibiting the activity of SHP2 phosphatase. Compounds of the invention can be used for the treatment of disorders associated with SHP2 deregulation. The present invention also relates to pharmaceutical compositions containing said compounds and to their method of synthesis.