Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
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.
Bioorganic medicinal chemistry letters