Structure-Activity Relationship Study of Subtype-Selective Positive Modulators of K Ca 2 Channels

• Published in: Journal of medicinal chemistry Vol. 65; no. 1; pp. 303 - 322
• Main Authors: El-Sayed, Naglaa Salem, Nam, Young-Woo, Egorova, Polina A, Nguyen, Hai Minh, Orfali, Razan, Rahman, Mohammad Asikur, Yang, Grace, Wulff, Heike, Bezprozvanny, Ilya, Parang, Keykavous, Zhang, Miao
• Format: Journal Article
• Language: English
• Published: United States 13.01.2022
• Subjects: Animals; Cerebellum - drug effects; Disease Models, Animal; Female; Ion Channel Gating; Male; Membrane Transport Modulators - chemistry; Membrane Transport Modulators - pharmacology; Mice; Potassium Channels, Calcium-Activated - agonists; Potassium Channels, Calcium-Activated - metabolism; Purkinje Cells - drug effects; Pyrimidines - chemistry; Spinocerebellar Ataxias - drug therapy; Spinocerebellar Ataxias - metabolism; Spinocerebellar Ataxias - pathology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01473

A series of modified -cyclohexyl-2-(3,5-dimethyl-1 -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 2 channel activity. Among the -benzene- -[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 conferred a ∼10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound conferred a ∼7-fold higher potency on potentiating K 2.2a channels, compared to that of the parent template CyPPA. Both compounds retained the K 2.2a/K 2.3 subtype selectivity. Based on the initial evaluation, compounds and 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.