TMEM16A Modulator Crystalline Forms for Mucus Clearance

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Solution Overview

Problem

Current treatments for respiratory diseases such as cystic fibrosis and chronic bronchitis are inadequate in effectively enhancing mucus clearance due to transient and incomplete modulation of TMEM16A channels.

Innovation Solution

Development of novel crystalline forms of the compound N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide, specifically Form A and Form B hydrate, which act as positive modulators of TMEM16A channels, thereby enhancing anion secretion and mucus clearance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If current treatments modulate TMEM16A channels, then anion secretion is enhanced, but the duration of action is transient and incomplete

Engineering Contradiction:

Improveduration of TMEM16A channel modulationVSAvoidcompleteness of mucus clearance enhancement

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent modifies the chemical structure of the TMEM16A modulator compound by introducing specific substituents (R1, R2, R3, R4 groups) to create derivatives with improved pharmacokinetic properties. This structural parameter change aims to extend the duration of channel modulation while maintaining therapeutic efficacy, directly addressing the transient nature of current treatments

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent describes methods to convert the compound between different solid crystalline polymorphic forms (Form I, Form II, Form III). These phase transitions affect the compound's stability, solubility, and release characteristics, which can influence the duration and reliability of TMEM16A channel modulation in vivo

Inventive Principle:

Principle #36Phase transitions

2Productivity

If mucus gel solids increase in respiratory diseases, then mucus clearance is reduced, but increasing hydration to improve clearance may cause other issues

Engineering Contradiction:

Improvemucus clearance efficiencyVSAvoidmucus gel hydration balance

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

The patent uses TMEM16A channel modulators as intermediary agents to indirectly enhance mucus clearance. Instead of directly altering mucus composition, the compound activates chloride channels to increase fluid secretion, which hydrates the mucus gel and improves clearance without directly modifying the mucus gel structure itself

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent replaces mechanical approaches to mucus clearance (such as direct mucolytics that break down mucus mechanically/chemically) with a physiological approach using ion channel modulation. This substitutes a biochemical mechanism (chloride channel activation leading to fluid secretion) for direct mechanical or chemical mucus breakdown, achieving clearance while maintaining mucus gel stability

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS12281077B2Solid forms of n-tert-butyl-4[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

Publication Date: 2025.04.22 TMEM16A LTD

AI summary

The invention relates to novel forms of N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1). In particular, the invention relates to the Form A and Form B crystalline polymorphs and the amorphous form.