MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation
| Autor: | Andrew M. Haidle, Alan B. Northrup, Alexander A. Szewczak, Lee Warren, Jason D. Katz, James P. Jewell, Mansuo Hayashi, Hugh Nuthall, Andreas Harsch, Michael D. Altman, Ian W. Davies, Dapeng Chen, Kaleen Konrad Childers, Michael Hutton, Anna A. Zabierek, Matthew G. Stanton, Yongquan Hou, Ben Munoz |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Pharmaceutical Science Pyrimidinones Computational biology Protein Serine-Threonine Kinases Pharmacology Biochemistry Structure-Activity Relationship 03 medical and health sciences Alzheimer Disease Drug Discovery Animals Humans Pyrroles Protein Kinase Inhibitors Molecular Biology Ligand efficiency Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Rats Isoenzymes 030104 developmental biology Go/no go Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:109-113 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.08.066 |
| Popis: | Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts. |
| Databáze: | OpenAIRE |
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