Naphthyridine MEK Inhibitors for Blood-Brain Barrier Penetration
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Solution Overview
Problem
Current MEK inhibitors face challenges in penetrating the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) to effectively treat tumors in the central nervous system (CNS), limiting their efficacy in treating MEK-associated tumors.
Innovation Solution
Development of novel 3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione compounds and their pharmaceutically acceptable salts that act as MEK inhibitors, which can penetrate these barriers and are used alone or in combination with other anticancer therapies to treat MEK-associated tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current MEK inhibitors are used to treat tumors, then MEK activity is inhibited, but the drugs cannot effectively penetrate the blood-brain barrier and blood-CSF barrier to treat CNS tumors
Solution Approach 1:
The patent modifies the chemical structure of MEK inhibitors by changing molecular parameters such as adding lipophilic groups (isopropyl, cyclopropyl, phenyl) and adjusting molecular weight and logP values to optimize blood-brain barrier penetration while maintaining MEK inhibitory activity. This is achieved through systematic structural modifications in the naphthyridine core compounds.
Solution Approach 2:
The patent creates composite molecular structures combining the MEK inhibitor pharmacophore with specific substituents that facilitate blood-brain barrier penetration. The compounds integrate multiple functional groups (amino, hydroxy, alkoxy, halogen) into a unified molecular architecture that simultaneously achieves target inhibition and barrier penetration.
2Quantity of substance
If MEK inhibitors are administered systemically, then they can reach peripheral tumors, but their concentration in the CNS remains insufficient due to efflux transporters
Solution Approach 1:
The patent exploits the structural characteristics that make compounds substrates for efflux transporters in a beneficial way by designing molecules with specific lipophilic and steric properties that allow them to evade P-glycoprotein and BCRP recognition while still being actively transported into the CNS through modified efflux mechanisms.
Solution Approach 2:
The patent introduces specific local structural features at key positions of the molecule (such as substituents at positions 7 and 8 of the naphthyridine ring) that create localized properties favoring CNS penetration. These local modifications include bulky lipophilic groups and specific hydrogen bonding capabilities that override efflux transporter action at the blood-brain interface.
Data Source
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AI summary
The invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R4 are as defined herein. The invention further relates to pharmaceutical compositions comprising such compounds and salts, and to methods and uses of such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer, in a subject in need thereof. The invention further relates to solid forms of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4- dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.