Structure–Activity Relationship Study of Subtype-Selective Positive Modulators of K_Ca2 Channels

Abstract

A series of modified <i>N</i>-cyclohexyl-2-(3,5-dimethyl-1<i>H</i>-pyrazol-1-yl)-6-methylpyrimidin-4-amine (CyPPA) analogues were synthesized by replacing the cyclohexane moiety with different 4-substituted cyclohexane rings, tyrosine analogues, or mono- and dihalophenyl rings and were subsequently studied for their potentiation of K_Ca2 channel activity. Among the <i>N</i>-benzene-<i>N</i>-[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 <b>2q</b> conferred a ∼10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound <b>2o</b> conferred a ∼7-fold higher potency on potentiating K_Ca2.2a channels, compared to that of the parent template CyPPA. Both compounds retained the K_Ca2.2a/K_Ca2.3 subtype selectivity. Based on the initial evaluation, compounds <b>2o</b> and <b>2q</b> were selected for testing in an electrophysiological model of spinocerebellar ataxia type 2 (SCA2). Both compounds were able to normalize the abnormal firing of Purkinje cells in cerebellar slices from SCA2 mice, suggesting the potential therapeutic usefulness of these compounds for treating symptoms of ataxia.