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.