Bicyclic Melatonin Agonist Metabolic Stability
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Solution Overview
Problem
Current melatonin receptor agonists have limitations in terms of chemical structure and metabolic stability, which affects their efficacy as therapeutic agents for sleep disorders and other melatonin-related diseases.
Innovation Solution
Development of a novel bicyclic compound with a specific chemical structure, represented by formula (I), which exhibits superior affinity for melatonin receptors and improved metabolic stability, potentially offering enhanced therapeutic effects as a pharmaceutical agent.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If melatonin is used as a therapeutic agent, then it can treat sleep disorders and melatonin-related diseases, but it is easily metabolized by metabolic enzymes in vivo leading to poor metabolic stability
Solution Approach 1:
The patent modifies the chemical structure of melatonin by changing parameters such as introducing a bicyclic ring system (combining 5-membered ring A and 6-membered ring B), adding substituents at specific positions, and adjusting molecular weight and lipophilicity. These parameter changes result in compounds with superior metabolic stability and reduced clearance rates compared to natural melatonin.
Solution Approach 2:
The patent creates composite molecular structures by fusing different ring systems (5-membered ring A containing oxygen or nitrogen with 6-membered ring B) to form novel bicyclic compounds. This composite approach combines the beneficial properties of different structural motifs to achieve both high affinity for melatonin receptors and improved metabolic stability.
2Reliability
If existing melatonin receptor agonists are used, then they can act on melatonin receptors, but they have limited chemical structure diversity and inferior affinity compared to natural melatonin
Solution Approach 1:
The patent divides the melatonin receptor binding site into two distinct regions: a 5-membered ring A (containing oxygen or nitrogen) and a 6-membered ring B, connected by a single bond. This segmentation allows independent optimization of each region for specific binding interactions, resulting in compounds with superior affinity while maintaining structural diversity through various substituent combinations.
Solution Approach 2:
The patent introduces different functional groups and substituents at specific local positions within the bicyclic structure (e.g., position 1, 2, 3 on ring A and position 4, 5, 6 on ring B). This local quality approach enables precise tuning of molecular properties to enhance receptor affinity while preserving overall structural variety across different compounds.
3Duration of action of moving object
If melatonin is used for treatment, then it can synchronize biological clock, but it has poor intracerebral mobility and is rapidly cleared from the body
Solution Approach 1:
The patent systematically changes molecular parameters including increasing molecular weight within an optimal range, adjusting the ratio of carbon to hydrogen atoms, modifying oxygen-to-carbon ratios, and optimizing logP values. These parameter changes collectively extend half-life and reduce clearance rates, enabling prolonged duration of action for treating sleep disorders and melatonin-related conditions.
Data Source
AI summary
The present invention provides a compound represented by the formula wherein R1 is a hydrocarbon group optionally having substituent(s), amino optionally having substituent(s), hydroxy optionally having a substituent or a heterocyclic group optionally having substituent(s); R2 is a hydrogen atom or a hydrocarbon group optionally having substituent(s); Xa and Xb are each C, N, O or S; Xc and Xd are each C or N; m is 0-2; n is 1-3; ring A is a 5-membered ring optionally having substituent(s); ring B is a 6-membered ring optionally having substituent(s); and ring C is a 3- to 5-membered ring optionally having substituent(s), provided that when Xa, Xc and Xd are each C, then Xb is N or S, or a salt thereof, which is useful as an agent for the prophylaxis or treatment of a disease relating to an action of melatonin, and the like.