Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia

  • Bioorg Med Chem Lett. 2016 Jan 1;26(1):126-32. doi: 10.1016/j.bmcl.2015.11.013.
Izzat T Raheem  1 ,  John D Schreier  1 ,  Joy Fuerst  2 ,  Liza Gantert  3 ,  Eric D Hostetler  3 ,  Sarah Huszar  4 ,  Aniket Joshi  3 ,  Monika Kandebo  5 ,  Somang H Kim  6 ,  Jing Li  7 ,  Bennett Ma  6 ,  Georgia McGaughey  8 ,  Sujata Sharma  9 ,  William D Shipe  1 ,  Jason Uslaner  4 ,  George H Vandeveer  1 ,  Youwei Yan  9 ,  John J Renger  5 ,  Sean M Smith  5 ,  Paul J Coleman  1 ,  Christopher D Cox  1
Affiliations
  • 1. Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
  • 2. Basic Pharmaceutical Sciences, Merck Research Laboratories, West Point, PA 19486, United States.
  • 3. Imaging, Merck Research Laboratories, West Point, PA 19486, United States.
  • 4. In Vivo Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
  • 5. Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
  • 6. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
  • 7. Discovery Process Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
  • 8. Chemistry Modeling and Informatics, Merck Research Laboratories, West Point, PA 19486, United States.
  • 9. Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
PMID: 26602277 DOI: 10.1016/j.bmcl.2015.11.013
Abstract

Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, Prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.

Keywords
Antipsychotic activity; Cognitive improvement; Fragment-based drug discovery; Phosphodiesterase 10A; Positron emission tomography; Pyrazolopyrimidine; Rational design; Schizophrenia.
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