Nonpeptidic GnRH Receptor Antagonists Improve Bioavailability
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Solution Overview
Problem
Existing GnRH receptor antagonists face challenges with low bioavailability and adverse side effects, limiting their clinical use, particularly in treating sex-hormone related conditions.
Innovation Solution
Development of small molecule GnRH receptor antagonists with specific structural formulas, including stereoisomers, esters, solvates, and pharmaceutically acceptable salts, for administration in pharmaceutical compositions to treat a variety of sex-hormone related conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptidic GnRH antagonists are used, then gonadotropins are suppressed from the onset, but bioavailability is low and adverse side effects occur
Solution Approach 1:
The patent changes the chemical structure parameters from peptidic compounds to nonpeptidic small molecule compounds with specific structural formulas. This structural parameter change improves bioavailability while maintaining the ability to suppress gonadotropins effectively.
Solution Approach 2:
The invention develops compounds with specific composite molecular structures containing multiple functional groups (aromatic rings, heteroatoms, specific substituents) that work together to achieve both high receptor affinity and improved pharmacokinetic properties including bioavailability.
2Reliability
If peptidic GnRH antagonists are used, then gonadotropins are suppressed from the onset, but adverse side effects are caused by histamine release
Solution Approach 1:
The patent changes the chemical nature from peptidic to nonpeptidic small molecules, which fundamentally alters the interaction profile with histamine receptors while maintaining GnRH receptor antagonism. This parameter change eliminates the harmful histamine release side effect.
Solution Approach 2:
The invention extracts and eliminates the harmful property (histamine release capability) from the therapeutic agent by designing nonpeptidic structures that specifically target GnRH receptors without triggering histamine pathways, while preserving the desired therapeutic effect.
3Speed
If peptidic GnRH antagonists are used, then rapid gonadotropin suppression is achieved, but sustained delivery routes are required
Solution Approach 1:
The patent changes the molecular size and chemical properties from large peptidic structures to smaller nonpeptidic molecules, which improves absorption characteristics and enables oral or other non-invasive administration routes while maintaining rapid onset of action.
Data Source
AI summary
GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure:wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.