Partial V1a Agonists for Cirrhosis Complications

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current vasoconstrictor therapies for treating cardiovascular complications associated with cirrhosis, such as terlipressin, have limitations including narrow therapeutic index, excessive vasoconstriction, short duration of action, and the need for frequent dosing, which can lead to severe adverse events and are not practical for outpatient use.

Innovation Solution

Development of selective, partial V1a vasopressin agonists with a ceiling on vasoconstrictive potential, allowing for long duration of action and consistent vasoconstriction, reducing undesired fluctuations and enabling safer, more convenient treatment of cirrhotic complications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stress or pressure

If full vasopressin agonists are used to treat hypovolemia or hypotension, then arterial pressure is elevated, but severe vasoconstriction and tissue hypoperfusion occur

Engineering Contradiction:

Improvearterial pressureVSAvoidsevere vasoconstriction and tissue hypoperfusion

Core Design Contradiction:

Stress or pressureVSObject-affected harmful factors

Solution Approach 1:

The patent applies partial agonism at the V1a receptor, where the compound binds to the receptor but produces only a submaximal vasoconstrictive response even at full receptor occupancy. This inherent ceiling effect limits excessive vasoconstriction and tissue hypoperfusion while still providing sufficient pressor effect to elevate arterial pressure in hypovolemic or hypotensive patients.

Inventive Principle:

Principle #16Partial or excessive action

2Stress or pressure

If vasoconstrictor therapies are used to treat cirrhotic complications, then arterial pressure is maintained, but the narrow therapeutic index restricts use to severe cases

Engineering Contradiction:

Improvearterial blood pressureVSAvoidtherapeutic index

Core Design Contradiction:

Stress or pressureVSAdaptability or versatility

Solution Approach 1:

The partial V1a agonist exhibits a broader therapeutic index by providing a ceiling effect on vasoconstriction. This allows the compound to be used across a wider range of clinical scenarios including mild to moderate cirrhotic complications, whereas full agonists are restricted to severe cases due to their narrow therapeutic window.

Inventive Principle:

Principle #16Partial or excessive action

3Stress or pressure

If terlipressin is used for cirrhotic complications, then vasoconstriction is achieved, but frequent dosing is required due to short duration of action

Engineering Contradiction:

ImprovevasoconstrictionVSAvoidduration of action

Core Design Contradiction:

Stress or pressureVSDuration of action of moving object

Solution Approach 1:

The patent describes compounds with extended duration of action that maintain consistent vasoconstrictive effect over prolonged periods. This allows for less frequent dosing compared to terlipressin, improving patient compliance and enabling outpatient management of cirrhotic complications.

Inventive Principle:

Principle #20Continuity of useful action

4Stress or pressure

If higher concentrations of vasoconstrictors are used, then pressor effect is enhanced, but excessive vasoconstriction and adverse events increase

Engineering Contradiction:

Improvepressor effectVSAvoidexcessive vasoconstriction and adverse events

Core Design Contradiction:

Stress or pressureVSObject-generated harmful factors

Solution Approach 1:

The partial V1a agonist inherently limits the maximal vasoconstrictive response regardless of concentration increases. This ceiling effect on efficacy prevents dose-dependent excessive vasoconstriction and associated adverse events, allowing for enhanced pressor effect without proportional increase in harmful effects.

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS9644000B2V1a receptor agonists

Publication Date: 2017.05.09 OCELOT BIO INC

AI summary

Compounds of formula (I), salts thereof, and compositions and uses thereof are described. The compounds are useful as V1a vasopressin agonists, for the treatment of, e.g., complications of cirrhosis, including bacterial peritonitis, HRS2 and refractory ascites.