Triazole Derivatives for GHS Receptor Antagonists
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Solution Overview
Problem
Current compounds fail to demonstrate significant receptor antagonistic activity and bioavailability for treating physiological and pathophysiological conditions mediated by growth hormone secretagogue (GHS) receptors, lacking in vitro and in vivo data to support their claimed effects on GH release and receptor modulation.
Innovation Solution
Development of novel triazole derivatives with improved receptor affinity, specifically designed to bind to GHS receptors, exhibiting more than threefold increased binding affinity compared to previous compounds, and possessing enhanced ADME properties such as increased metabolic stability and bioavailability, allowing for effective modulation of GHS receptors as agonists, antagonists, or inverse agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current compounds are used for treating GHS receptor-mediated conditions, then treatment is attempted, but receptor antagonistic activity and bioavailability are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structure parameters of the compounds. Specifically, the invention changes the core heterocyclic structure to triazole derivatives, modifies substituent positions and types (R1-R6 groups), and adjusts molecular weight and lipophilicity parameters to optimize both receptor antagonistic activity and bioavailability properties
Solution Approach 2:
The patent employs composite material principles by creating hybrid molecular structures that combine multiple functional moieties within single compounds. The triazole core is复合 with various aromatic rings, amide groups, and substituent patterns to achieve multifunctional properties including enhanced receptor binding, improved metabolic stability, and optimized pharmacokinetic profile
2Reliability
If higher dosages are used to compensate for low receptor activity, then receptor modulation is attempted, but side effects increase and metabolic stability decreases
Solution Approach 1:
The patent optimizes the dosage parameter by improving intrinsic compound potency through structural modification. The triazole derivatives achieve higher receptor affinity and selectivity, allowing effective modulation at lower concentrations. This reduces the dosage required for therapeutic effect and consequently minimizes side effects and metabolic burden
3Reliability
If previous compounds are administered, then GHS receptor binding is attempted, but binding affinity is insufficient (less than threefold improvement needed)
Solution Approach 1:
The patent applies local quality principles by optimizing specific regions of the molecular structure. The triazole core (positions 1-3) is designed for optimal receptor interaction, while substituent groups at different positions (R1-R6) are independently optimized for specific functions such as hydrogen bonding, hydrophobic interactions, and steric fit within the receptor binding pocket
Solution Approach 2:
The patent systematically varies structural parameters including ring substitution patterns, chain length, aromaticity, and functional group types to achieve more than threefold improvement in binding affinity compared to previous compounds, while maintaining appropriate pharmacokinetic properties
Data Source
AI summary
The present invention provides novel triazole derivatives with improved receptor activity and bioavailability properties as ghrelin analogue ligands of growth hormone secretagogue receptors according to formula (I) that are useful in the treatment or prophylaxis of physiological and/or pathophysiological conditions in mammals, preferably humans, that are mediated by GHS receptors. The present invention further provides GHS receptor antagonists and agonists that can be used for modulation of these receptors and are useful for treating above conditions, in particular alcohol disorder; drug abuse; growth retardation; cachexia; short-, medium- and/or long term regulation of energy balance; short-, medium- and/or long term regulation (stimulation and/or inhibition) of food intake; intake of rewarding food; adipogenesis; adiposity and/or obesity; body weight gain and/or reduction; diabetes, diabetes type I, diabetes type II; tumor cell proliferation; inflammation; inflammatory effects; gastric postoperative ileus; postoperative ileus and/or gastrectomy (ghrelin replacement therapy)".