8beta-Substituted Estrogens for Selective ERbeta Activation

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Solution Overview

Problem

Current estrogen therapies for hormone-deficiency-induced symptoms and ovarian-induced infertility often result in undesirable side effects, such as endometrial hyperplasia, intracyclic menstrual bleeding, and ovarian overstimulation, due to the lack of selective estrogen receptor subtype specificity, particularly in targeting estrogen receptor beta (ERβ) over estrogen receptor alpha (ERα).

Innovation Solution

Development of 8β-substituted estra-1,3,5(10)-triene derivatives with specific substituents that exhibit a higher affinity for estrogen receptor preparations from rat prostates than from rat uteri, providing enhanced potency and metabolic stability, thereby preferentially affecting the ovary with minimal impact on the uterus.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional estrogens are used for hormone replacement therapy, then hormone-deficiency symptoms are treated, but endometrial hyperplasia and intracyclic menstrual bleeding occur due to non-selective estrogen receptor activation

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidendometrial hyperplasia

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing estrogens with specific molecular characteristics (8β-substitution patterns, 16α-fluoro group) that confer selective affinity for ERβ over ERα. This enables the same compound to have different effects in different tissues: protective effects in ERβ-dominant tissues (bone, brain, cardiovascular system) while avoiding proliferative effects in ERα-dominant tissues (endometrium).

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying the chemical structure of estrogen molecules through specific substitutions at the 8β-position and 16α-fluoro introduction. These structural parameter changes result in altered receptor binding characteristics, achieving selective ERβ activation with dissociation from ERα, thereby treating hormone deficiency symptoms without causing endometrial side effects.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If estrogens are used to treat ovarian-induced infertility, then follicular maturation is stimulated, but ovarian overstimulation occurs due to lack of selective action

Engineering Contradiction:

Improvefertility treatment efficacyVSAvoidovarian overstimulation

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The selective ERβ-activating estrogens exhibit local quality by preferentially acting on ERβ receptors in the ovary while having minimal effect on ERα receptors in the uterus. This tissue-selective action allows effective stimulation of follicular maturation and ovulation without causing uterine side effects or excessive ovarian stimulation, improving the safety profile of fertility treatments.

Inventive Principle:

Principle #3Local quality

3Object-affected harmful factors

If SERMs are used as selective estrogens, then antiestrogenic action on endometrium is achieved, but effectiveness for acute postmenopausal symptoms is lost

Engineering Contradiction:

Improveendometrial protectionVSAvoidsymptom relief efficacy

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent inverts the conventional SERM approach by designing compounds that are pure agonists at ERβ rather than partial agonists/antagonists. Instead of using mixed agonist-antagonist activity (SERMs), the invention uses selective agonism at ERβ to achieve both endometrial protection and effective relief of postmenopausal symptoms, including hot flashes, through central nervous system ERβ activation.

Inventive Principle:

Principle #13The other way round (Inversion)

4Object-affected harmful factors

If estrogen/gestagen combination preparations are used, then endometrial hypertrophy is avoided, but intracyclic menstrual bleeding occurs

Engineering Contradiction:

Improveendometrial hypertrophy preventionVSAvoidintracyclic menstrual bleeding

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

The patent extracts the beneficial endometrial protective effect from the gestagen component by using selective ERβ-activating estrogens that inherently provide endometrial protection through ERβ activation. This eliminates the need for gestagen addition, thereby avoiding the harmful side effect of intracyclic menstrual bleeding while maintaining endometrial safety.

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentEP2176282B18-beta-substituted 16.alpha.-fluoro-estratrienes as selectively active estrogens

Publication Date: 2012.08.22 BAYER INTPROP GMBH

AI summary

The invention refers to 8ß-substituted estra-1,3,5(10)-triene derivatives of general formula (I), their use as pharmaceutical active ingredients, which have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo a preferential action in the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.