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

Naglaa Salem El-Sayed, Young Woo Nam, Polina A. Egorova, Hai Minh Nguyen, Razan Orfali, Mohammad Asikur Rahman, Grace Yang, Heike Wulff, Ilya Bezprozvanny, Keykavous Parang, Miao Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A series of modified N-cyclohexyl-2-(3,5-dimethyl-1H-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 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 a ∼10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound 2o conferred a ∼7-fold higher potency on potentiating KCa2.2a channels, compared to that of 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 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.

Original languageEnglish (US)
JournalJournal of medicinal chemistry
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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