GPR88 Modulator Composition With Improved PK and Lower Off-Target Activity

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Solution Overview

Problem

Existing GPR88 modulators exhibit suboptimal pharmacokinetic properties and off-target activity, which are undesirable for therapeutic applications in neuropsychiatric disorders.

Innovation Solution

Development of novel GPR88 modulators with improved pharmacokinetic properties and reduced off-target activity, specifically compounds of formulae (I) and (II) or their pharmaceutically acceptable salts, targeting GPR88 receptors to treat conditions like Tourette's Syndrome, Huntington's Disease, Parkinson's Disease, Schizophrenia, and ADHD.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing GPR88 modulators are used, then GPR88 receptor modulation is achieved, but pharmacokinetic properties are suboptimal and off-target activity occurs

Engineering Contradiction:

Improvepharmacokinetic propertiesVSAvoidoff-target activity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by systematically modifying molecular parameters of GPR88 modulators, including substituent groups (R1-R6), ring structures (Ring B, Ring C), and molecular weight constraints. These parameter modifications optimize pharmacokinetic properties while reducing off-target activity, as evidenced by the detailed structural definitions and selection criteria provided in the patent

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent implements local quality by specifying particular structural features at different positions of the molecule. For example, R1 is defined as C5-C8 alkyl with specific substituents, Ring B is selected from phenyl and heteroaryl, and each position has tailored requirements. This localized optimization ensures improved pharmacokinetic profile and reduced off-target effects at specific molecular regions

Inventive Principle:

Principle #3Local quality

2Reliability

If existing GPR88 modulators are used, then therapeutic effect on neuropsychiatric disorders is achieved, but pharmacokinetic properties limit therapeutic efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidpharmacokinetic duration

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies molecular parameters to extend duration of action and improve therapeutic efficacy. The structural definitions include specific alkyl chain lengths, heteroaryl ring selections, and substituent patterns that enhance pharmacokinetic duration. The molecular weight constraints and structural flexibility parameters are optimized to maintain therapeutic effect while improving pharmacokinetic profile

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250367158A1Modulators of g protein-coupled receptor 88

Publication Date: 2025.12.04 ACADIA PHARMACEUTICALS INC

AI summary

Alkoxy-substituted N-benzyl-2-phenylacetamide compounds and derivatives are G-protein coupled receptor (GPR) 88 modulators for use in the treatment of a disease mediated by GPR88. Indications include Tourette's Syndrome, Huntington's Disease (HD), Addiction, Parkinson's Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and/or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer's disease and basal ganglia disorders.