SUR1-Selective KATP Potentiators for Congenital Hyperinsulinism
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Solution Overview
Problem
Current KATP channel openers, such as diazoxide, lack tissue specificity, leading to significant side effects and are ineffective in severe cases of congenital hyperinsulinism due to mutations in the ABCC8 and KCNJ11 genes, while alternative treatments also have undesirable side effects.
Innovation Solution
Development of compounds that selectively bind to the SUR1/Kir6.2 channel, inhibiting glucose-stimulated insulin secretion, with improved bioavailability, stability, and safety, allowing oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If diazoxide is used to open KATP channels, then insulin secretion is inhibited, but tissue-specificity is lost leading to numerous side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I) that selectively bind to SUR1 subunits in pancreatic beta-cells while avoiding SUR2-containing channels in other tissues. This is achieved through specific structural features including the heterocyclic ring system and substituent patterns that confer preference for SUR1 over SUR2, thereby achieving tissue-specific action and reducing off-target side effects.
Solution Approach 2:
The invention segments the KATP channel targeting by developing compounds that specifically interact with the SUR1 subunit rather than all SUR subunits. The molecular structure is designed to recognize and bind selectively to SUR1's unique binding pocket, effectively segmenting the broad KATP channel target into a more specific SUR1-selective target, which reduces activation of SUR2-containing channels in vascular and other tissues.
2Reliability
If first-generation KCOs like diazoxide are used, then KATP channels are opened, but selectivity for SUR1 is limited and activity shifts to SUR2-containing channels
Solution Approach 1:
The patent applies parameter changes by modifying key molecular parameters of KCO structures - specifically the heterocyclic core (Formula I), substituent types (R1-R6), and molecular geometry - to shift the binding affinity profile from non-selective (first-generation) to SUR1-preferential. These parameter modifications change the compounds' physical-chemical properties to better match SUR1's binding characteristics, reducing activity at SUR2-containing channels.
3Reliability
If KCOs are used to treat CHI, then beta-cell activity is reduced, but potency is moderate and selectivity is limited
Solution Approach 1:
The invention employs composite molecular design by combining specific heterocyclic structures (Formula I) with tailored substituent patterns (R1-R6 groups) to create compounds with enhanced and balanced properties. This composite approach integrates multiple structural elements that collectively provide both high potency for beta-cell KATP channel opening and improved selectivity for SUR1, achieving a synergistic effect that neither component alone could provide.
Data Source
AI summary
The present disclosure relates to compounds of general formula (I) or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, methods for their preparation, the use of said compounds for use as a medicament, and their use in the treatment and/or prevention of a disease or disorder, such as a metabolic disorder (e.g., hyperinsulinism, e.g., congenital hyperinsulinism). The present disclosure also relates to a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically acceptable carrier and its use as a medicament, in particular its use in the treatment of a disease or disorder, such as a metabolic disorder (e.g., hyperinsulinism, e.g., congenital hyperinsulinism).