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). Positive 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 chemical matter for modulating SK channels, a FLIPR screen was performed and identified the commercially-available compound CyPPA as a screening hit. Subsequent electrophysiological 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 chemical 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 chemical 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 toxicology studies, CAD-1883 has recently been evaluated in a Phase 1 clinical 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.

Discovery of CAD-1883: Clinical-stage positive allosteric modulator of the SK channel for the treatment of essential tremor and spinocerebellar ataxia

2019 Fall National Meeting

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