Medicine and Health

Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia

M. E. Layton, J. C. Kern, et al.

Discover how the inhibition of Phosphodiesterase 10A (PDE10A) could revolutionize schizophrenia treatment by normalizing striatal activity. This exciting research conducted by Mark E Layton and colleagues unveils MK-8189, a powerful PDE10A inhibitor currently undergoing Phase 2b clinical development.

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Abstract

Phosphodiesterase 10A (PDE10A) inhibition offers a novel mechanism for treating schizophrenia by normalizing dysfunctional striatal activity. This paper details the discovery of MK-8189 (compound 18), a highly potent and selective PDE10A inhibitor, stemming from the optimization of a fragment hit. The optimization addressed liabilities such as poor pharmacokinetic properties, off-target activities, and low solubility, resulting in a compound currently in Phase 2b clinical development for schizophrenia.

Publisher

Journal of Medicinal Chemistry

Published On

Jan 01, 2023

Authors

Mark E Layton, Jeffrey C Kern, Timothy J Hartingh, William D Shipe, Izzat Raheem, Monika Kandebo, Robert P Hayes, Sarah Huszar, Donnie Eddins, Bennett Ma, Joy Fuerst, Gordon K Wollenberg, Jing Li, Jeff Fritzen, Georgia B Mcgaughey, Jason M Uslaner, Sean M Smith, Paul J Coleman, Christopher D Cox

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