Heterocyclic Circadian Modulators for Phase Shift and Period Control
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Solution Overview
Problem
Current treatments for circadian rhythm disorders, such as jet lag and shift work disorder, are inconvenient, ineffective for certain conditions, and have variable responses due to their reliance on external cues like light or melatonin, which do not directly target the molecular circadian mechanism.
Innovation Solution
Heterocyclic compounds that modulate circadian rhythms by directly influencing the molecular components of the circadian oscillator, increasing the period and shifting the phase of the circadian rhythm, thereby synchronizing it with external time.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If light or melatonin is used to treat circadian rhythm disorders, then the treatment can synchronize the circadian rhythm with external cues, but the treatment is inconvenient and has variable responses due to indirect action on the circadian mechanism
Solution Approach 1:
The patent uses small molecules that directly interact with circadian clock proteins (PER2, CRY1) as intermediaries between external treatment and the molecular circadian mechanism. These compounds serve as chemical mediators that can cross cell membranes and directly modulate the circadian oscillator at the molecular level, replacing the indirect action of light and melatonin.
Solution Approach 2:
The patent replaces the mechanical/physical system of light exposure (requiring specific timing, intensity, and duration) with a chemical system of small molecule administration. This substitution eliminates the need for complex light delivery systems and allows for more flexible, convenient dosing while achieving direct modulation of circadian clock proteins.
2Reliability
If light therapy is used to treat circadian rhythm disorders, then the circadian rhythm can be synchronized, but the treatment requires precise timing and has variable responses
Solution Approach 1:
The patent changes the parameters of circadian rhythm treatment from temporal parameters (light timing, duration, intensity) to chemical parameters (molecule structure, concentration, dosing frequency). The small molecules can be administered at different times and doses to achieve the desired phase shift, providing more flexible parameter optimization without strict temporal constraints.
3Adaptability or versatility
If melatonin or synthetic agonists are used, then circadian rhythm can be modulated, but the response varies significantly between patients and conditions
Solution Approach 1:
The patent employs a series of related small molecule compounds with slightly different structures and potencies that can be dynamically selected and adjusted based on the specific patient condition, genotype, and desired outcome. This dynamic approach allows optimization of treatment for individual patients, improving response consistency while maintaining adaptability to different circadian disorders.
Data Source
AI summary
Heterocyclic compounds of general formula I and their pharmaceutically acceptable salts where each of X, Y, Z is selected from CH2 and O. One of X, Y, Z is O, n is 1 or 2 or 3 and R1 is H or C1-C4 alkyl. R2 is selected from H, C1, C1-C4 alkoxy and NR21R22, where R21 and R22 are independently selected from H, C3-C6 cycloalkyl and C1-C8 alkyl, where one carbon atom in the C1-C8 alkyl may be replaced by one nitrogen or one oxygen atom. R21 is H or C1-C4 alkyl and R22 is selected from C6-C10 aryl-methyl, C6-10 aryl-ethyl, C3-C6 heteroaryl-methyl, and C3-C6 heteroaryl-ethyl, wherein the heteroaryl group contains 1-2 heteroatoms selected from O, S, N. R21 and R22 together with the nitrogen atom to which they are bound form a 3-to 8-membered ring containing one further heteroatom selected from O, S, N.