# Discovery of 7‑(Pyridin-3-yl)thieno[3,2‑b]pyridine-5-carboxamides as Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

## TL;DR

Researchers developed a new compound that modulates a brain receptor without causing liver toxicity, a common issue with older versions.

## Contribution

A novel scaffold for mGlu5 NAMs was developed, avoiding toxic moieties and improving brain penetration and hepatic clearance.

## Key findings

- Compound VU6035386 showed low nanomolar potency against human mGlu5.
- VU6035386 demonstrated improved brain penetration and predicted hepatic clearance compared to VU6031545.

## Abstract

Herein, we report
the structure–activity relationship (SAR)
to develop novel mGlu5 negative allosteric modulator (NAM)
scaffolds devoid of the aryl/heterobiaryl acetylene moiety found in
many historic mGlu5 NAMs, which has been linked to metabolic
liabilities and hepatotoxicity. This endeavor utilized a scaffold-hopping
strategy from the predecessor compound VU6031545, in
which we replace an ether-linked tetrahydrofuran with various carbon-linked
heteroaryl motifs to generate highly potent and selective mGlu5 NAMs. One such compound, VU6035386, displayed
low nanomolar potency against human mGlu5 and was highly
brain penetrant. Moreover, VU6035386 showed a vast improvement
in predicted human hepatic clearance versus predecessor compound VU6031545.