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

[Display omitted] 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 cryst...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-01, Vol.26 (1), p.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: Article
Language:English
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
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.11.013