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Updated: Mar 11, 2026

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Published on: January 22, 2019
MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation
Andrew M Haidle1, Kaleen K Childers1, Anna A Zabierek1
1Department of Chemistry, 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.
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