Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia
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Acknowledgments
The authors thank the Merck West Point NMR and Mass Spectrometry facilities for assistance in characterizing the compounds presented in this manuscript.
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2021, European Journal of Medicinal ChemistryCitation Excerpt :It has also shown excellent PK profile in preclinical animal models. During the pharmacodynamic studies, the compound 5 showed in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing and dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay [127]. Ginny D. Ho and co-workers identified dihydroimidazoisoquinoline as a chemotype having PDE10A inhibitory activity in the medicinal chemistry program at Merck Research Laboratory (Fig. 21).
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2015, Bioorganic and Medicinal Chemistry LettersThe PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents
2015, NeuropharmacologyCitation Excerpt :Due to the high level of expression in the striatum, it has been hypothesized that inhibition of PDE10A can regulate activation of MSNs and significantly influence output of the basal ganglia. Accordingly, preclinical studies have demonstrated that oral administration of selective PDE10A inhibitors elevate both cAMP and cGMP in the rodent striatum (Raheem et al., 2012; Smith et al., 2013; Grauer et al., 2009; Schmidt et al., 2008; Verhoest et al., 2009). Further investigation of signaling pathways downstream of cAMP demonstrated that PDE10A inhibitors induce significant changes in the phosphorylation of GluR1 subunit of the AMPA receptor and increase phosphorylation of extracellular-signal-regulated kinase (ERK) and cAMP-response element-binding protein (CREB).
A comparative study of binding affinities for 6,7-dimethoxy-4-pyrrolidylquinazolines as phosphodiesterase 10A inhibitors using the linear interaction energy method
2015, Journal of Molecular Graphics and ModellingCitation Excerpt :AD provides a first structural alert on the dataset and is primarily used to check whether a new molecular entity is within the chemical space of the training set or not. For the AD experiment a set of 160 PDE10 inhibitors was retrieved from ChEMBL database [48] and this dataset consist of 6 different scaffolds [19,49–53] which share no structural similarity with the training set that we used for the binding affinity model development [40]. The ΔGobs values span an energy difference of 3.16 kcal/mol (Fig. 8A).