Discovery of VU6077564: A Selective M₁ Antagonist That Promotes Neurite Outgrowth in Adult Sensory Neurons

Previously, we reported the potent and highly selective M₁ antagonists VU0415248 and VU0452865; however, these compounds were limited by high predicted hepatic clearance in rat. This work reports the development of cyclobutylsulfonamide-based analogs of VU0415248 and VU0452865. From this exercise, we identified VU6077564, a peripherally restricted and selective M₁ antagonist. Furthermore, we demonstrate the ability of VU6077564 to promote neurite outgrowth in adult rat dorsal root ganglia sensory neurons, highlighting the potential of selective M₁ antagonists for the treatment of peripheral neuropathy.