Herein we describe the drug discovery efforts of Cadent Therapeutics and its collaborators to identify development candidate CAD-1883, an allosteric modulator of the small conductance calcium-activated potassium (SK) channel, for the treatment of essential tremor (ET) and spinocerebellar ataxia (SCA). Pos. allosteric modulation (PAM) of SK channels represents a potential therapeutic approach for the treatment of ET, SCA, and other movement disorders which are characterized by dysregulated firing of the cerebellum. SK modulation will affect the afterhyperpolarization event of an action potential in Purkinje cells of the cerebellum and is expected to restore a normalized firing pattern. In order to identify novel chem. matter for modulating SK channels, a FLIPR screen was performed and identified the com.-available compound CyPPA as a screening hit. Subsequent electrophysiol. assays confirmed CyPPA's PAM activity on the SK2 and SK3 subtypes. While CyPPA was a promising starting point, significant optimization was required in order to address several issues such as its lack of oral bioavailability, limited brain penetration, low metabolic stability, and inhibition of various Cyp isoforms. Structure-activity relationships were developed to understand how to increase solubility, enhance brain/plasma ratio, maintain sufficient free fraction, and reduce some off-target liabilities. Further improvements in chem. stability, PK properties, off-target profile, and CMC developability were achieved as well. After the design and synthesis of more than 1400 analogs, CAD-1883 was identified as having the most exceptional properties in the chem. series. CAD-1883 demonstrated efficacy in a harmaline-induced rodent model of essential tremor and a mouse efficacy model of hereditary ataxia. After successful synthetic scale-up and completion of GLP toxicol. studies, CAD-1883 has recently been evaluated in a Phase 1 clin. study in human healthy volunteers. Based on the promising safety, tolerability, and pharmacokinetics, Cadent Therapeutics has initiated a Phase 2 study in ET with CAD-1883.