Heteroaromatic D1 Ligands Modulating Receptor Binding

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Solution Overview

Problem

Current pharmaceutical agents are inadequate in modulating dopamine D1 receptors effectively to treat diseases associated with dysregulated activation, such as schizophrenia, cognitive impairment, and other neurological disorders.

Innovation Solution

Development of a compound of Formula I, which includes specific heteroaromatic structures that act as dopamine D1 ligands, potentially as agonists or partial agonists, to modulate D1 receptors and address dysregulated activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current pharmaceutical agents are used to modulate dopamine D1 receptors, then some level of receptor interaction is achieved, but the effectiveness is inadequate for treating neurological disorders

Engineering Contradiction:

Improveeffectiveness of D1 receptor modulationVSAvoidtherapeutic benefit for neurological disorders

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies molecular parameters of D1 receptor ligands by incorporating specific heteroaromatic moieties (pyridine, pyrimidine, triazine rings) and adjusting substituent patterns to optimize receptor binding affinity and selectivity, thereby improving therapeutic effectiveness for neurological disorders

Inventive Principle:

Principle #35Parameter changes

2Reliability

If D1 receptors are activated to treat neurological disorders, then receptor function is improved, but dysregulated activation must be avoided

Engineering Contradiction:

Improvereceptor functionVSAvoiddysregulated activation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent designs ligands with specific local molecular features including heteroaromatic rings at particular positions and specific substituent groups (halogens, alkyl groups, alkoxy groups) to achieve selective activation of D1 receptors while avoiding dysregulated activation through precise spatial arrangement of functional groups

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs carefully designed small molecule ligands as intermediaries that selectively bind to and modulate D1 receptors, providing controlled activation that improves receptor function while preventing dysregulated activation through optimized molecular structure and binding characteristics

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentEP2917219B1Heteroaromatic compounds and their use as dopamine d1 ligands

Publication Date: 2017.09.27 PFIZER INC

AI summary

The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof and N-oxides thereof; processes and intermediates for preparation of; and compositions and uses thereof. The present invention further provides D1 agonists with reduced D1R desensitization, D1 agonists with a reduced β- arrestin recruitment activity relative to Dopamine, D1 agonists interacting significantly with the Ser188 but not significantly with the Ser202 of a D1R when binding to the D1R, D1 agonists interacting less strongly with the Asp103 and interacting less strongly with the Ser198 of a D1R when binding to the D1R, and their uses.