This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M (ICs<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL=5.37mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.
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