Aprocitentan and SGLT-2 Inhibitor Combination for Endothelin Disease

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Solution Overview

Problem

Existing endothelin receptor antagonists (ERAs) face challenges such as fluid retention and increased risk of cardiovascular events, particularly in treating resistant hypertension and chronic kidney disease.

Innovation Solution

The use of aprocitentan, a dual endothelin receptor antagonist, in combination with a sodium glucose cotransporter 2 (SGLT-2) inhibitor, to treat endothelin-related diseases, potentially mitigating side effects like fluid retention.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If endothelin receptor antagonists are used to treat resistant hypertension and chronic kidney disease, then blood pressure control and renal protection are improved, but fluid retention and cardiovascular events increase

Engineering Contradiction:

Improvetreatment efficacyVSAvoidfluid retention

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent combines aprocitentan (dual endothelin receptor antagonist) with an SGLT-2 inhibitor in a single pharmaceutical composition. The SGLT-2 inhibitor promotes sodium and glucose excretion, counteracting the fluid retention caused by endothelin receptor antagonism, while maintaining blood pressure control and renal protective effects

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The SGLT-2 inhibitor acts as an intermediary agent that mediates between the therapeutic effect of the endothelin receptor antagonist and the harmful fluid retention. By promoting urinary excretion of sodium and glucose, it provides a compensatory mechanism that offsets the sodium and water retention caused by ERA therapy

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If endothelin receptor antagonists are used to treat endothelin-related diseases, then vasoconstriction and proliferation are inhibited, but side effects such as fluid overload occur

Engineering Contradiction:

Improvetherapeutic benefitVSAvoidfluid overload

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful fluid retention effect of endothelin receptor antagonism into a beneficial outcome by combining it with an SGLT-2 inhibitor. The inhibitor's primary function of promoting sodium and glucose excretion becomes a therapeutic advantage that counterbalances the ERA-induced fluid overload, allowing higher dosages and improved treatment outcomes

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Productivity

If dosage of aprocitentan is increased to improve treatment outcomes, then therapeutic efficacy is enhanced, but risk of cardiovascular events increases

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidcardiovascular events

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The pharmaceutical composition merges aprocitentan with an SGLT-2 inhibitor in fixed ratios, allowing administration of higher aprocitentan dosages (e.g., 10-100 mg daily) that would normally be associated with increased cardiovascular risk. The combined formulation ensures that the SGLT-2 inhibitor's natriuretic and diuretic effects are present to counteract potential fluid overload and cardiovascular events

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20250120973A1Combination of a 4-pyrimidinesulfamide derivative with an SGLT-2 inhibitor for the treatment of endothelin related diseases

Publication Date: 2025.04.17 IDORSIA PHARMACEUTICALS LTD

AI summary

The present invention concerns the compound aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide:and its use as endothelin receptor antagonist, in combination with an SGLT-2 inhibitor. The invention further relates to pharmaceutical compositions comprising aprocitentan in combination with said SGLT-2 inhibitor. The invention further relates to such pharmaceutical compositions comprising crystalline forms of aprocitentan.