1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders

Journal of Enzyme Inhibition and Medicinal Chemistry

Ana Martinez¹  Daniel I. Perez¹  Zdenek Fisar²  Concepcion Perez³  Lukas Hroch⁴  Kamil Musilek⁵  Kamil Kuca⁵  Lucie Vinklarova⁵  Ondrej Benek⁶  Laura Aitken⁷  Frank Gunn-Moore⁷ 

[1] Centro de Investigaciones Biologicas-CSIC, Madrid, Spain;Charles University and General University Hospital in Prague, First Faculty of Medicine, Department of Psychiatry, Prague, Czech Republi;Instituto de Quimica Medica-CSIC, Madrid, Spain;University Hospital in Hradec Kralove, Biomedical Research Center, Hradec Kralove, Czech Republic;University of Hradec Kralove, Faculty of Science, Department of Chemistry, Hradec Kralove, Czech Republic;University Hospital in Hradec Kralove, Biomedical Research Center, Hradec Kralove, Czech Republic;University of Hradec Kralove, Faculty of Science, Department of Chemistry, Hradec Kralove, Czech Republic;University Hospital in Hradec Kralove, Biomedical Research Center, Hradec Kralove, Czech Republic;National Institute of Mental Health, Klecany, Czech Republic;University of St. Andrews, Medical and Biological Sciences Building, School of Biology, St. Andrews, UK;

关键词: Alzheimer’s disease;    amyloid-beta binding alcohol dehydrogenase (ABAD);    benzothiazole;    casein kinase 1 (CK1);    neurodegeneration;   

DOI  :  10.1080/14756366.2018.1445736

来源: publisher

【 摘 要 】

Several neurodegenerative disorders including Alzheimer’s disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease’s progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.

【 授权许可】

CC BY