Structure-Activity Relationship Study of Subtype-Selective Positive Modulators of KCa2 Channels

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A series of modified N-cyclohexyl-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine (CyPPA) analogs were synthesized by replacing the cyclohexane moiety with different 4-substituted cyclohexane rings, tyrosine analogs, or mono- and dihalophenyl rings, and were subsequently studied for their potentiation of KCa2 channel activity. Among the N-benzene-N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine derivatives, halogen decoration at positions 2 and 5 of benzene-substituted 4-pyrimidineamine in compound 2q conferred ~10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound 2o conferred ~7-fold higher potency on potentiating KCa2.2a channels, compared to the parent template CyPPA. Both compounds retained the KCa2.2a/KCa2.3 subtype selectivity. Based on the initial evaluation, compounds 2o and 2q were selected for testing in an electrophysiological model of spinocerebellar ataxia type 2 (SCA2). Both compounds were able to normalize abnormal firing of Purkinje cells in cerebellar slices from SCA2 mice, suggesting the potential therapeutic usefulness of these compounds for treating symptoms of ataxia.


This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Journal of Medicinal Chemistry, volume 65, issue 1, in 2022 following peer review. This article may not exactly replicate the final published version. The definitive publisher-authenticated version is available online at


American Chemical Society