# Discovery of VU6025733 (AG06827): A Highly Selective, Orally Bioavailable, and Structurally Distinct M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy

## TL;DR

A new compound, VU6025733, was developed as a highly selective and effective modulator of the M4 receptor, but its development was halted due to liver toxicity risks.

## Contribution

A novel scaffold and compound with high potency and selectivity for M4 receptors was identified and optimized.

## Key findings

- VU6025733 showed high potency with EC50 values of 23 nM for human M4 and 55 nM for rat M4.
- The compound exhibited excellent DMPK properties and in vivo efficacy in a rat hyperlocomotion model.
- However, hepatotoxicity risk prevented further development of the compound.

## Abstract

This
work describes
progress toward an M4 PAM
preclinical
candidate. The SAR to address potency, clearance, subtype selectivity,
CNS exposure, and P-gp efflux are detailed within. A novel 1-(7,8-dimethyl-[1,2,4]­triazolo­[4,3-b]­pyridazin-6-yl)­piperidin-4-ol scaffold was identified,
and optimization provided a highly potent analog VU6025733 (hM4 EC50 = 23 nM; rM4 EC50 = 55 nM). Further characterization revealed a highly selective compound
across muscarinic acetylcholine receptor subtypes with exceptional
DMPK properties (in vivo rat CLp = 5.9
mL/min/kg; t
1/2 = 4.8 h; CYP1A2 &
CYP2C9 IC50s > 30 μM, CYP2D6 IC50 >
9
μM; CYP3A4 IC50 > 25 μM). Moreover, VU6025733 demonstrated robust in vivo efficacy
in a rat amphetamine-induced
hyperlocomotion model in a dose-dependent manner. However, hepatotoxicity
risk precluded further development.