# Further Optimization of the mGlu1 PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685

## TL;DR

Scientists improved a drug that targets a brain receptor, but found it caused side effects in animals, raising concerns about its safety.

## Contribution

The discovery of a new mGlu1 PAM compound with improved structure and tested efficacy in animal models.

## Key findings

- VU6033685/BI1752 is a potent and selective mGlu1 PAM with efficacy in amphetamine-induced hyperlocomotion and novel object recognition.
- VU6033685/BI1752 showed a clear pharmacokinetic–pharmacodynamic relationship.
- Adverse events were observed in both rats and dogs for VU6033685/BI1752 and another chemotype.

## Abstract

Herein, we report the further chemical optimization of
the metabotropic
glutamate receptor subtype 1 (mGlu1) positive allosteric
modulator (PAM) VU6024578/BI02982816 and the discovery of VU6033685/BI1752.
PAM VU6033685/BI1752 was developed through an iterative process wherein,
after the furanyl moiety (a potential toxicophore) was replaced by
an N-linked pyrazole, a diversity screen identified
a quinoline core, which was further truncated to a pyridine scaffold.
PAM VU6033685/BI1752 proved to be a potent and selective mGlu1 PAM with efficacy in both amphetamine-induced hyperlocomotion
(AHL) and novel object recognition (NOR) with a clear pharmacokinetic–pharmacodynamic
(PK/PD) relationship. VU6024578/BI02982816 was efficacious and well
tolerated in rats but not dogs, whereas VU6033685/BI1752 elicited
adverse events (AEs) in both rats and dogs. These AEs, noted in two
distinct mGlu1 PAM chemotypes, cast a shadow on an otherwise
promising molecular target to address multiple symptom clusters in
schizophrenic patients.