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

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 1; pp. 126 - 132
• Main Authors: Raheem, Izzat T., Schreier, John D., Fuerst, Joy, Gantert, Liza, Hostetler, Eric D., Huszar, Sarah, Joshi, Aniket, Kandebo, Monika, Kim, Somang H., Li, Jing, Ma, Bennett, McGaughey, Georgia, Sharma, Sujata, Shipe, William D., Uslaner, Jason, Vandeveer, George H., Yan, Youwei, Renger, John J., Smith, Sean M., Coleman, Paul J., Cox, Christopher D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2016
• Subjects: Animals; Antipsychotic activity; Cognitive improvement; Crystallography, X-Ray; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Fragment-based drug discovery; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Macaca mulatta; Models, Molecular; Molecular Structure; Phosphodiesterase 10A; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Positron emission tomography; Pyrazolopyrimidine; Rational design; Rats; Rats, Wistar; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - enzymology; Structure-Activity Relationship; Phosphodiesterase 10A; Pyrazolopyrimidine; Rational design; Fragment-based drug discovery; Schizophrenia; Positron emission tomography; Antipsychotic activity; Cognitive improvement
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.11.013

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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 [11C]MK-8193, a novel PDE10A PET tracer.