Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization
| Autor: | Heng-Xiu Yan, Jun Zou, Ze-Rong Wang, Shan Feng, Yang Lingling, Pan Ji, Guo-Bo Li, Qi-Zheng Sun, Shuang Ma, Shengyong Yang |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Pharmacology Virtual screening Dose-Response Relationship Drug Molecular Structure Pyrimidine Casein Kinase I Stereochemistry Organic Chemistry General Medicine Hit to lead Diamines Combinatorial chemistry High-Throughput Screening Assays Structure-Activity Relationship chemistry.chemical_compound Pyrimidines chemistry Diamine Drug Discovery Casein kinase 1 Pharmacophore Protein Kinase Inhibitors Lead compound |
| Zdroj: | European Journal of Medicinal Chemistry. 56:30-38 |
| ISSN: | 0223-5234 |
| Popis: | Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC50 value of 78 nM. |
| Databáze: | OpenAIRE |
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