Discovery of VU6025733 (AG06827): A Highly Selective, Orally Bioavailable, and Structurally Distinct M₄ Muscarinic...

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 CL_p = 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.