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

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

  • J Med Chem. 2023 Jan 26;66(2):1157-1171. doi: 10.1021/acs.jmedchem.2c01521.
Mark E Layton 1,  Jeffrey C Kern 1,  Timothy J Hartingh 1,  William D Shipe 1,  Izzat Raheem 1,  Monika Kandebo 2,  Robert P Hayes 3,  Sarah Huszar 4,  Donnie Eddins 4,  Bennett Ma 5,  Joy Fuerst 6,  Gordon K Wollenberg 7,  Jing Li 8,  Jeff Fritzen 8,  Georgia B McGaughey 9,  Jason M Uslaner 2,  Sean M Smith 2,  Paul J Coleman 1,  Christopher D Cox 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 2 Neuroscience, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 3 Structural Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 4 In Vivo Pharmacology, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 5 Pharmacokinetics, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 6 Discovery Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 7 Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 8 Discovery Process Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 9 Chemistry Modeling and Informatics, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
PMID: 36624931 DOI: 10.1021/acs.jmedchem.2c01521
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.

Figures
Products