Discovery of MK-8189, a Highly Potent and Selective PDE10A

Index

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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