Macrocyclic Ghrelin Modulators for Selective GI Motility
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current pharmacological agents targeting the ghrelin receptor for therapeutic action have shown limited efficacy and are associated with undesirable side effects, particularly in treating gastrointestinal disorders and metabolic disorders, where they often exacerbate gastrointestinal motility issues.
Innovation Solution
Development of novel conformationally-defined macrocyclic compounds that selectively modulate the ghrelin receptor, acting as agonists to stimulate gastrointestinal motility without concurrent growth hormone secretion, thereby addressing the underlying pathophysiological disturbances in conditions like post-operative ileus, gastroparesis, and opioid-induced bowel dysfunction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current pharmacological agents targeting the ghrelin receptor are used to treat gastrointestinal disorders, then some therapeutic effect is achieved, but gastrointestinal motility issues are exacerbated and growth hormone secretion is concurrently stimulated causing side effects
Solution Approach 1:
The patent applies segmentation by separating the therapeutic gastrointestinal effects from the unwanted growth hormone secretion effects. The macrocyclic compounds are designed to selectively activate ghrelin receptor subtypes in the gastrointestinal tract while avoiding activation of receptors in the pituitary gland, thus segmenting the pharmacological action to achieve therapeutic benefit without systemic side effects.
Solution Approach 2:
The invention implements local quality by creating compounds with selective affinity for specific ghrelin receptor subtypes expressed in gastrointestinal tissues. The macrocyclic structure is engineered to interact preferentially with GI tract receptors, providing localized therapeutic action in the gastrointestinal system while minimizing activation of growth hormone pathways in other tissues.
2Productivity
If ghrelin receptor agonists are used to stimulate gastrointestinal motility, then gastrointestinal function is improved, but growth hormone secretion is also stimulated causing undesirable side effects
Solution Approach 1:
The patent segments the physiological effects by designing macrocyclic compounds that selectively target gastrointestinal ghrelin receptors. The molecular structure is optimized to fit specific receptor subtypes in the GI tract, separating the motility-stimulating effect from the growth hormone-releasing effect, thereby achieving improved gastrointestinal productivity without the harmful side effect of concurrent growth hormone secretion.
Solution Approach 2:
The invention employs parameter changes by modifying the chemical structure to macrocyclic forms with specific conformational constraints. These structural parameter changes alter the pharmacological profile to achieve selective receptor subtype activation, transforming the non-selective agonist profile into a selective one that stimulates GI motility while avoiding growth hormone secretion.
3Reliability
If conventional ghrelin receptor modulators are administered, then some therapeutic benefit is obtained, but the treatment is limited by undesirable side effects and reduced efficacy
Solution Approach 1:
The patent applies the composite materials principle by creating macrocyclic compounds that integrate multiple functional groups and structural elements into a single molecular entity. The composite structure combines rigid cyclic frameworks with flexible linkers and specific functional moieties, creating a unified molecule that achieves both high receptor selectivity and potent therapeutic activity, thereby improving reliability while managing the inherent complexity through integrated design.
Data Source
AI summary
The present invention provides novel conformationally-defined macrocyclic compounds that can function as selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, bone disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.