Alpha-amino ester tocolytic agent for selective uterine relaxation
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Solution Overview
Problem
Current therapies for preventing preterm labor lack myometrial selectivity and are associated with significant side effects, failing to effectively inhibit uterine contractions and prolong pregnancy safely.
Innovation Solution
Development of alpha-amino esters of hydroxypropylthiazolidine carboxamide derivatives and their salts, which selectively bind to the prostaglandin F2α receptor, inhibiting uterine contractions and prolonging pregnancy by reducing the amplitude of uterine contractions and delaying labor.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tocolytic agents are used to inhibit uterine contractions, then labor can be delayed, but the agents lack myometrial selectivity and cause serious side effects for the mother and fetus
Solution Approach 1:
The patent applies local quality by designing a compound with selective affinity for the FP receptor specifically in myometrial tissue. The compound (3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}-amino)-3-(4-fluorophenyl)propyl L-valinate exhibits high selectivity for FP receptors in uterine smooth muscle cells, achieving localized therapeutic action while minimizing systemic side effects on the mother and fetus.
Solution Approach 2:
The patent employs parameter changes by optimizing the chemical structure of the tocolytic agent to achieve high affinity for the FP receptor (Ki values in the nanomolar range). The specific molecular parameters including the thiazolidine ring, biphenyl-sulfonyl group, and amino ester configuration are tuned to maximize selective binding to FP receptors while reducing off-target effects.
2Duration of action of moving object
If available tocolytic agents are administered, then labor can be prolonged for some duration, but they do not prolong labor for more than 48 hours
Solution Approach 1:
The patent applies preliminary action by administering the compound before preterm labor becomes irreversible, allowing sufficient time for fetal maturation. The high affinity binding to FP receptors (nanomolar Ki values) ensures sustained tocolytic effect that can prolong pregnancy beyond 48 hours, providing a therapeutic window for corticosteroid administration and fetal lung maturation.
Solution Approach 2:
The patent incorporates feedback mechanisms through the reversible binding nature of the compound to FP receptors. The compound maintains therapeutic levels of FP receptor occupancy to sustain uterine relaxation, with the duration of action determined by the balance between administration frequency and receptor binding kinetics, allowing flexible dosing to achieve desired prolongation duration.
3Reliability
If prostaglandin synthesis inhibitors are used, then some tocolytic effect is achieved, but fetal safety concerns arise due to un-licensed use
Solution Approach 1:
The patent uses an intermediary approach by targeting the FP receptor directly rather than inhibiting prostaglandin synthesis. This downstream receptor antagonism achieves tocolytic effect without interfering with prostaglandin production, which is essential for fetal lung maturation and other physiological processes, thereby eliminating fetal safety concerns associated with synthesis inhibitors.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds demonstrate high affinity for the prostaglandin F2α receptor, reducing uterine contractions by up to 50% and prolonging pregnancy, thereby improving fetal maturation and reducing neonatal mortality and morbidity.
Implementation Method 1
the compounds of the invention bind human prostaglandin F2α receptor with an affinity of about 1 nM
Implementation Method 2
receptors that provoke calcium entry or calcium release from intracellular stores stimulate contractility
Data Source
AI summary
The invention provides α-amino esters of a hydroxypropylthiazolidine carboxamide derivative, (2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide, as well as salts and crystal polymorphs thereof, that can be used to inhibit prostaglandin F receptor. The invention further encompasses methods of treating disorders such as preterm labor at the early gestational stage by the administration of these substances to a patient in need of treatment.