{"doi":"10.1016/j.ejmech.2018.07.050","title":"Development of novel 2,4-bispyridyl thiophene–based compounds as highly potent and selective Dyrk1A inhibitors. Part I: Benzamide and benzylamide derivatives","abstract":null,"journal":"European Journal of Medicinal Chemistry","year":2018,"id":672250,"datarank":0.48283137373023016,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"self_citation_contribution":0.48283137373023016,"citation_network_contribution":0.0,"self_endowment_contribution":0.48283137373023016,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1756370,"name":"Mohammad Abdel-Halim","orcid":null,"position":1,"is_corresponding":false},{"id":1756372,"name":"Mohamed Salah","orcid":null,"position":2,"is_corresponding":false},{"id":1756374,"name":"Ashraf H. Abadi","orcid":null,"position":3,"is_corresponding":false},{"id":1756375,"name":"Walter Becker","orcid":null,"position":4,"is_corresponding":false},{"id":424497,"name":"Matthias Engel","orcid":"0000-0001-5065-8634","position":5,"is_corresponding":false},{"id":1756368,"name":"Sarah S. Darwish","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Development of novel 2,4-bispyridyl thiophene–based compounds as highly potent and selective Dyrk1A inhibitors. Part I: Benzamide and benzylamide derivatives","abstract":"The protein kinase Dyrk1A modulates several processes relevant to the development or progression of Alzheimer's disease (AD), e. g. through phosphorylation of tau protein, amyloid precursor protein (APP) as well as proteins involved in the regulation of alternative splicing of tau pre-mRNA. Therefore, Dyrk1A has been proposed as a potential target for the treatment of AD. However, the co-inhibition of other closely related kinases of the same family of protein kinases (e.g. Dyrk1B and Dyrk2) or kinases from other families such as Clk1 limits the use of Dyrk1A inhibitors, as this may cause unpredictable side effects especially over long treatment periods. Herein, we describe the design and synthesis of a series of amide functionalized 2,4-bispyridyl thiophene compounds, of which the 4-fluorobenzyl amide derivative (31b) displayed the highest potency against Dyrk1A and remarkable selectivity over closely related kinases (IC<sub>50</sub>: Dyrk1A = 14.3 nM; Dyrk1B = 383 nM, Clk1 > 2 μM). This degree of selectivity over the frequently hit off-targets has rarely been achieved to date. Additionally, 31b inhibited Dyrk1A in intact cells with high efficacy (IC<sub>50</sub> = 79 nM). Furthermore, 31b displayed a high metabolic stability in vitro with a half-life of 2 h. Altogether, the benzamide and benzylamide extension at the 2,4-bispyridyl thiophene core improved several key properties, giving access to compound suitable for future in vivo studies.","is_dataset_classified":null,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"30193214","pmcid":null,"openalex_id":"https://openalex.org/W2883877962","authors":[],"funders":[{"funder_name":"Science & Technology Development Fund in Egypt","grant_id":"17391","title":null},{"funder_name":"\"PPP Ägypten 15\"","grant_id":"57190395","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"EN381/2-3","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"unidentified","title":"unidentified"},{"funder_name":"GERSS 2015","grant_id":"","title":null},{"funder_name":"DAAD","grant_id":"","title":null},{"funder_name":"GradUS Global 2017","grant_id":"","title":null}],"total_grants":7,"fwci":1.4395,"citation_percentile":0.83019502,"influential_citations":0,"citation_trend":[{"year":2018,"count":1},{"year":2019,"count":2},{"year":2020,"count":3},{"year":2021,"count":3},{"year":2022,"count":6},{"year":2023,"count":3},{"year":2024,"count":4},{"year":2025,"count":2}],"oa_status":"green","license":"Elsevier TDM","oa_locations":[{"url":"https://doi.org/10.7270/q2280b8q","host_type":"repository"},{"url":"https://doi.org/10.7270/q2280b8q","host_type":"repository"},{"url":"https://api.elsevier.com/content/article/PII:S0223523418306068?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0223523418306068?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.ejmech.2018.07.050","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/30193214","host_type":"repository"},{"url":"https://dx.doi.org/10.22028/d291-29394","host_type":""},{"url":"https://dx.doi.org/10.1016/j.ejmech.2018.07.050","host_type":""}],"fields_of_study":["Genetics and Neurodevelopmental Disorders","Cancer-related Molecular Pathways","Signaling Pathways in Disease","0301 basic medicine","0303 health sciences","03 medical and health sciences","Amides","Benzamides","Dose-Response Relationship, Drug","Humans","Molecular Structure","Protein Kinase Inhibitors","Protein Serine-Threonine Kinases","Protein-Tyrosine Kinases","Structure-Activity Relationship","Thiophenes","Dyrk Kinases"],"mesh_terms":["Dyrk Kinases","Amides","Benzamides","Dose-Response Relationship, Drug","Humans","Protein-Tyrosine Kinases","Structure-Activity Relationship","Thiophenes","Molecular Structure","Protein Serine-Threonine Kinases","Protein Kinase Inhibitors"],"keywords":["DYRK1A","Chemistry","Kinase","Benzamide","Phosphorylation","Protein-Serine-Threonine Kinases","Lead compound","Biochemistry","Protein kinase A","In vitro","Stereochemistry","Alzheimer's disease","Selectivity","Metabolic Stability","Bispyridyl Thiophene Amides","Dose-Response Relationship, Drug","Molecular Structure","Thiophenes","Protein Serine-Threonine Kinases","Protein-Tyrosine Kinases","Dyrk Kinases","Amides","Structure-Activity Relationship","Benzamides","Humans","Protein Kinase Inhibitors"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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