1H-Pyrrolo[3,2-b]pyridine GluN2B-Selective Negative Allosteric Modulators

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• GluN2B-containing NMDA receptors are implicated in various neurological disorders.
• Developing selective modulators with favorable pharmacokinetic properties is crucial for therapeutic applications.

Purpose of the Study:

• To discover and optimize selective GluN2B negative allosteric modulators (NAMs) based on a 1H-pyrrolo[3,2-b]pyridine scaffold.
• To enhance brain penetration and reduce off-target effects like CYP450 inhibition and hERG binding.

Main Methods:

• Synthesis and in vitro evaluation of a series of 1H-pyrrolo[3,2-b]pyridine derivatives.
• Lead optimization focused on improving ADME (Absorption, Distribution, Metabolism, Excretion) properties and reducing toxicity.
• In vivo assessment of target engagement using receptor occupancy studies in rats.

Main Results:

• Several compounds, including 9, 25, 30, and 34, exhibited good in vitro GluN2B potency and predicted absorption.
• Optimization successfully reduced metabolic turnover and cytochrome P450 inhibition.
• All tested compounds achieved >75% GluN2B receptor occupancy in rats at 10 mg/kg oral dose.
• Compound 9 demonstrated dose-dependent receptor occupancy with an ED50 of 2.0 mg/kg.

Conclusions:

• The 1H-pyrrolo[3,2-b]pyridine core is a viable scaffold for developing selective GluN2B NAMs.
• Optimized compounds display promising in vitro and in vivo profiles for potential therapeutic intervention in CNS disorders.
• Compound 9 represents a lead candidate with significant GluN2B receptor occupancy in vivo.