Development of VU6036864: A Triazolopyridine-Based High-Quality Antagonist Tool Compound of the M 5 Muscarinic Acetylcholine Receptor.

While the muscarinic acetylcholine receptor mAChR subtype 5 (M 5 ) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M 5 antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, VU6036864 ( 45 ) showed exquisite potency (human M 5 IC 50 = 20 nM), good subtype selectivity (>500 fold selectivity against human M 1-4 ), desirable brain exposure ( K p = 0.68, K p,uu = 0.65), and high oral bioavailability (% F > 100%). VU6036864 ( 45 ) and its close analogues will support further studies of M 5 as advanced antagonist tool compounds and play an important role in the emerging biology of M 5 .