Fused Polycyclic Thienopyrimidine Diones for Oral GnRH Antagonism
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Solution Overview
Problem
Current treatments for endometriosis, such as non-steroidal anti-inflammatory drugs, oral contraceptives, aromatase inhibitors, and GnRH agonists, have significant side effects and limitations, and there is a need for more effective small molecule GnRH receptor antagonists to manage the disease effectively.
Innovation Solution
Development of a novel GnRH receptor antagonist with a fused polycyclic structure, represented by formula (II) or its pharmaceutically acceptable salts, which inhibits the GnRH receptor and has high oral bioavailability, long half-life, and excellent pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current clinical treatments (oral contraceptives, progesterone, aromatase inhibitors, GnRH agonists) are used to treat endometriosis, then the disease symptoms can be controlled, but significant side effects occur (obesity, cardiotoxicity, abnormal lipid metabolism, perimenopausal symptoms)
Solution Approach 1:
The patent applies parameter changes by developing small molecule GnRH receptor antagonists with optimized chemical structures (formula I and II) that modify the molecular parameters to achieve selective binding to GnRH receptors. This allows effective suppression of gonadotropin secretion without triggering the side effects associated with traditional treatments, as the molecular structure is specifically designed to interact only with the target receptor
Solution Approach 2:
The patent uses small molecule compounds as intermediaries that competitively bind to GnRH receptors, blocking the natural GnRH from binding. These small molecules act as mediators between the hypothalamus-pituitary-ovarian axis, providing precise pharmacological control that avoids the systemic side effects of traditional hormonal treatments while maintaining therapeutic effectiveness
2Reliability
If polypeptide GnRH receptor agonists are used, then GnRH receptor activity can be modulated, but obstacles occur in oral absorption, dosage form, dose volume, drug stability, sustained action, and metabolic stability
Solution Approach 1:
The patent employs small molecule compounds with appropriate pharmacokinetic properties that can be administered orally and provide sustained therapeutic effect through repeated dosing. These small molecules are designed to have adequate metabolic stability and half-life to maintain therapeutic levels without requiring complex delivery systems, making them suitable for routine oral administration
Solution Approach 2:
The patent changes the chemical parameter from polypeptide to small molecule structure, which fundamentally improves oral bioavailability. The small molecule compounds in formula I and II have optimized molecular weight, lipophilicity, and metabolic stability parameters that enable effective oral absorption and first-pass metabolism, eliminating the administration obstacles associated with polypeptide agonists
3Object-generated harmful factors
If existing small molecule GnRH receptor antagonists (Elagolix, Relugolix, Linzagolix) are developed, then fast-acting inhibition with few side effects is achieved, but continued research is needed to develop more effective compounds
Solution Approach 1:
The patent applies segmentation by dividing the GnRH receptor binding interface into distinct molecular regions represented by different substituents in formula I and II. This allows systematic optimization of each region to enhance binding affinity and selectivity, enabling the development of more effective antagonists with improved therapeutic indices compared to existing compounds
Solution Approach 2:
The patent uses composite molecular structures combining fused polycyclic cores with various aromatic and heterocyclic substituents. This composite approach allows integration of multiple pharmacophoric elements that work synergistically to achieve high receptor affinity, selective binding, and optimized pharmacokinetic properties, resulting in superior effectiveness compared to single-structure antagonists
Data Source
AI summary
Disclosed in the present invention are a series of fused polycyclic substituted 5-carboxylic acid thienopyrimidine dione compounds and the use thereof. Specifically disclosed are a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.