Aprocitentan Dual Endothelin Blockade for Resistant Hypertension

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Solution Overview

Problem

Existing endothelin receptor antagonists (ERAs) face challenges in treating resistant hypertension and chronic kidney disease due to side effects such as fluid retention, limiting their effectiveness and safety, particularly when used in combination with other antihypertensive therapies.

Innovation Solution

Aprocitentan, a dual endothelin receptor antagonist, is administered in combination with standard background therapies like angiotensin receptor blockers, calcium channel blockers, and diuretics, providing effective blood pressure control with a benign side effect profile, avoiding the need for risk assessments or dose reductions typically required by other ERAs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing endothelin receptor antagonists are used to treat resistant hypertension, then blood pressure control is achieved, but fluid retention side effects occur

Engineering Contradiction:

Improveblood pressure controlVSAvoidfluid retention

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of endothelin receptor antagonists through various substitutions (R1-R6 groups) to alter pharmacological properties. This resolves the contradiction by changing molecular parameters to achieve blood pressure control while reducing fluid retention side effects through optimized receptor binding characteristics

Inventive Principle:

Principle #35Parameter changes

2Reliability

If endothelin receptor antagonists are used in combination with other antihypertensive therapies, then treatment effectiveness is improved, but safety concerns increase due to side effects

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidsafety concerns

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs composite materials by creating combination therapies that integrate the novel endothelin receptor antagonist with other antihypertensive agents. This composite approach achieves synergistic blood pressure control while the specific molecular design of the ERA component mitigates fluid retention, thereby improving overall safety profile

Inventive Principle:

Principle #40Composite materials

3Reliability

If standard ERAs are administered at conventional doses, then endothelin receptor blockade is achieved, but dose reductions are required to manage side effects

Engineering Contradiction:

Improvereceptor blockade efficacyVSAvoiddosage management

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent utilizes parameter changes by optimizing the pharmacokinetic and pharmacodynamic parameters of the ERA through structural modifications. This enables effective receptor blockade at lower doses, simplifying dosage management and eliminating the need for dose reductions to manage side effects

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250345332A1Aprocitentan for the treatment of hypertension

Publication Date: 2025.11.13 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: Formula (I) and its use as endothelin receptor antagonist in a method of treating hypertension including resistant hypertension in a subject in need thereof, said method comprising administering to the subject a pharmaceutical composition comprising a clinically proven effective amount of aprocitentan, or a pharmaceutically acceptable salt thereof.