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

Authors

Gregro AR Alison R , Park C Charlotte , Long MF Madeline F , Baker LA Logan A , Bollinger KA Katrina A , Ringuette AE Anna E , Peng L Li , Luscombe VB Vincent B , Billard NB Natasha B , Rodriguez AL Alice L , Niswender CM Colleen M , Peng W Weimin , Dickerson JW Jonathan W , Rook JM Jerri M , O'Neill J Jordan , Chang S Sichen , Boonen HCM Harrie C M , Jensen T Thomas , Thomsen MS Morten S , Bridges TM Thomas M , Boutaud O Olivier , Conn PJ P Jeffrey , Engers DW Darren W , Lindsley CW Craig W , Temple KJ Kayla J .
ACS chemical neuroscience. 2026 1 25; 17(3).
649-665

Abstract

This work describes progress toward an M 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-]pyridazin-6-yl)piperidin-4-ol scaffold was identified, and optimization provided a highly potent analog (hM EC = 23 nM; rM EC = 55 nM). Further characterization revealed a highly selective compound across muscarinic acetylcholine receptor subtypes with exceptional DMPK properties ( rat CL = 5.9 mL/min/kg; = 4.8 h; CYP1A2 & CYP2C9 ICs > 30 μM, CYP2D6 IC > 9 μM; CYP3A4 IC > 25 μM). Moreover, demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion model in a dose-dependent manner. However, hepatotoxicity risk precluded further development.

Tags: 2026