Macrocyclic Ghrelin Agonists for Motility Disorders
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Solution Overview
Problem
Current pharmacological agents targeting the ghrelin receptor for therapeutic purposes often face issues with efficacy over prolonged treatment and undesired side effects, and there is a need for agents that can effectively modulate gastrointestinal motility without stimulating growth hormone secretion.
Innovation Solution
Development of novel conformationally-defined macrocyclic compounds that act as agonists of the ghrelin receptor, specifically designed to stimulate gastrointestinal motility across various gastrointestinal disorders without concurrent GH secretion stimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current pharmacological agents targeting the ghrelin receptor are used for therapeutic purposes, then gastrointestinal motility can be stimulated, but growth hormone secretion is also stimulated causing undesired side effects
Solution Approach 1:
The invention segments the physiological effects of ghrelin receptor activation by developing macrocyclic compounds that selectively stimulate gastrointestinal motility while avoiding growth hormone secretion. The macrocyclic structure allows the compound to bind to and activate the ghrelin receptor in the gastrointestinal tract without triggering the downstream signaling pathway that leads to GH release, thereby separating the therapeutic effect from the harmful side effect.
Solution Approach 2:
The macrocyclic compounds exhibit local quality by demonstrating selective tissue distribution and receptor activation patterns. The compounds preferentially bind to ghrelin receptors in the gastrointestinal tract where they exert prokinetic effects, while showing reduced affinity or different signaling outcomes at receptors in the pituitary-growth hormone axis,从而实现 localized therapeutic action without systemic side effects.
2Duration of action of stationary object
If ghrelin receptor agonists are used for prolonged treatment, then therapeutic benefits are maintained, but efficacy decreases over time
Solution Approach 1:
The invention inverts the conventional approach by using a macrocyclic structural framework that provides enhanced metabolic stability and resistance to enzymatic degradation. This structural inversion from typical linear or small-cyclic peptidomimetics to macrocyclic architectures prevents the rapid metabolism that leads to tolerance development, allowing sustained therapeutic efficacy over prolonged treatment periods.
Solution Approach 2:
The macrocyclic compounds represent composite molecular structures combining rigid cyclic frameworks with flexible linkers and pharmacophoric elements. This composite architecture provides both structural stability for prolonged circulation and appropriate receptor binding characteristics, preventing the development of tolerance while maintaining therapeutic efficacy throughout extended treatment durations.
3Adaptability or versatility
If conventional ghrelin receptor modulators are used, then both gastrointestinal and growth hormone effects are achieved, but selectivity for gastrointestinal motility is insufficient
Solution Approach 1:
The invention extracts the gastrointestinal-specific signaling pathway from the overall ghrelin receptor activation profile. The macrocyclic compounds are designed to preferentially activate Gi/o protein-coupled signaling in gastrointestinal tissues while avoiding the Gs protein-mediated pathway that leads to growth hormone release, thereby extracting the desired prokinetic effect from the undesired GH-stimulating effect.
Solution Approach 2:
The macrocyclic compounds act as selective intermediaries that mediate gastrointestinal motility stimulation through preferential binding to and activation of ghrelin receptors in the GI tract. The macrocyclic structure serves as a mediator that directs the pharmacological action specifically to gastrointestinal tissues through selective tissue distribution and receptor binding, while acting as a non-activating or weak-activating ligand at pituitary ghrelin receptors involved in GH secretion.
Data Source
AI summary
The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective agonists of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Such compounds are useful as medicaments for treatment and prevention of a range of medical conditions characterized by disturbed gastrointestinal motility including, but not limited to, post-surgical gastroparesis and post-operative ileus in combination with opioid-induced bowel dysfunction. These agents are effective for multiple disorders at dose levels equivalent to those required to treat a single disorder.