Alpha-amino ester FP receptor antagonists for pre-term labor

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Solution Overview

Problem

Current therapies for preventing pre-term labor lack uterine selectivity and are associated with significant side effects, and existing tocolytic agents do not effectively prolong pregnancy beyond 48 hours, highlighting a need for more effective and selective inhibitors of uterine contractions.

Innovation Solution

Development of alpha-amino esters of hydroxypropylthiazolidine carboxamide derivatives that 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

VSEngineering Contradiction Analysis

1Reliability

If existing tocolytic agents are used to prevent pre-term labor, then uterine contractions are inhibited, but the agents lack uterine selectivity and cause serious side effects for mother and fetus

Engineering Contradiction:

Improveeffectiveness of uterine contraction inhibitionVSAvoidside effects on mother and fetus

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing a compound with selective affinity for the FP receptor specifically expressed in uterine tissue. The compound (3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}-amino)-3-(4-fluorophenyl)propyl L-valinate exhibits preferential binding to the FP receptor in the myometrium, achieving local selective action in the uterus while minimizing systemic effects on other organs and tissues, thereby reducing side effects on mother and fetus

Inventive Principle:

Principle #3Local quality

2Duration of action of moving object

If existing tocolytic agents are administered, then labor is prolonged temporarily, but the duration of action does not exceed 48 hours

Engineering Contradiction:

Improveduration of labor prolongationVSAvoidsustained efficacy

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent applies preliminary action by administering the compound before the onset or early stages of pre-term labor to prevent the activation of the contractile pathway. The compound pre-occupies the FP receptor, blocking the action of endogenous PGF2α before it can trigger sustained uterine contractions, thereby extending the window of labor suppression beyond the 48-hour limitation of existing agents

Inventive Principle:

Principle #10Preliminary action

3Power

If prostaglandin F2α receptor is activated, then uterine contractility is stimulated, but this leads to pre-term labor and delivery

Engineering Contradiction:

Improveuterine contractilityVSAvoidpregnancy maintenance

Core Design Contradiction:

PowerVSReliability

Solution Approach 1:

The patent applies preliminary anti-action by using the compound as an FP receptor antagonist that binds to and blocks the receptor before endogenous PGF2α can activate it. This preliminary blocking action prevents the stimulation of uterine contractility and the subsequent cascade leading to pre-term labor, thereby maintaining pregnancy

Inventive Principle:

Principle #9Preliminary anti-action

Data Source

PatentUS10259795B2Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof

Publication Date: 2019.04.16 MERCK SERONO SA

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 pre-term labor at the early gestational stage by the administration of these substances to a patient in need of treatment.