Pyrazolo[1,5-a]pyrimidine Derivatives for GABA B Receptor Modulation

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Solution Overview

Problem

Current GABA B receptor ligands, such as baclofen, face issues with poor blood-brain barrier penetration, narrow therapeutic window, receptor desensitization, and tolerance development, limiting their therapeutic effectiveness for various neurological and psychiatric disorders.

Innovation Solution

Development of pyrazolo[1,5-a]pyrimidine derivatives that act as GABA B receptor positive allosteric modulators, offering improved metabolic stability and brain penetration, potentially reducing side effects and tolerance, and providing therapeutic benefits for psychiatric, neurodevelopmental, and neurological disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current GABA B receptor ligands (such as baclofen) are used, then therapeutic effects are achieved, but blood-brain barrier penetration is poor

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidblood-brain barrier penetration

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of GABA B receptor ligands through the introduction of specific aromatic groups and structural motifs. This structural optimization enhances lipophilicity and molecular properties to improve blood-brain barrier penetration while maintaining therapeutic efficacy at the receptor level.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current GABA B receptor ligands are used, then muscle relaxation effects are achieved, but tolerance and receptor desensitization occur

Engineering Contradiction:

Improvemuscle relaxation effectVSAvoidtolerance development

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent inverts the conventional orthosteric agonist approach by developing positive allosteric modulators that bind to a different site on the GABA B receptor. This allosteric mechanism enhances endogenous GABA activity without directly activating the receptor, thereby avoiding tolerance and desensitization while maintaining muscle relaxation effects.

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If narrow therapeutic window ligands are used, then specific GABA B receptor effects are achieved, but side effects increase

Engineering Contradiction:

Improvereceptor specificityVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent optimizes the therapeutic window by modifying ligand parameters including molecular weight, lipophilicity, and structural configuration. These changes enable selective GABA B receptor modulation with improved safety margins, reducing side effects while preserving the desired therapeutic effects through enhanced receptor specificity.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3596079B1Pharmacologically active aryl-substituted pyrazolo[1,5-a]pyrimidine derivatives

Publication Date: 2021.09.01 RICHTER GEDEON NYRT

AI summary

The present invention relates to new pyrazolo[1,5-a]pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof that serve as GABAB receptor positive allosteric modulators. The invention also relates to the process for producing such compounds. The invention further relates to pharmaceutical compositions comprising such compounds optionally in combination with two or more different therapeutic agents and the use of such compounds in methods for treating diseases and conditions mediated and modulated by the GABAB receptor positive allosteric mechanism. The invention also provides a method for manufacture of medicaments useful in the treatment of such disorders.