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MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation |
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| Authors: | Andrew M Haidle Kaleen K Childers Anna A Zabierek Jason D Katz James P Jewell Yongquan Hou Michael D Altman Alexander Szewczak Dapeng Chen Andreas Harsch Mansuo Hayashi Lee Warren Michael Hutton Hugh Nuthall Matt G Stanton Ian W Davies Ben Munoz Alan Northrup |
| Institution: | 1. Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;3. Department of In Vitro Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;4. Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA |
| Abstract: | 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. |
| Keywords: | MARK Kinase Pharmacokinetics Optimization Physical properties Disposition study In vitro–in vivo correlation |
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