2. Academic Validation
  3. Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia

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

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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