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

ABSTRACT: PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.

SUBMITTER: Layton ME

PROVIDER: S-EPMC9884086 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Layton Mark E ME Kern Jeffrey C JC Hartingh Timothy J TJ Shipe William D WD Raheem Izzat I Kandebo Monika M Hayes Robert P RP Huszar Sarah S Eddins Donnie D Ma Bennett B Fuerst Joy J Wollenberg Gordon K GK Li Jing J Fritzen Jeff J McGaughey Georgia B GB Uslaner Jason M JM Smith Sean M SM Coleman Paul J PJ Cox Christopher D CD

Journal of medicinal chemistry 20230109 2

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-t ...[more]

PMID: 36624931

Dataset Information

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

Publications

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

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