The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia

Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

“…The Schering-Plough Corp. part of Merck have also been engaged in a PDE10A discovery program and have a patent application claiming a series of substituted pyrazoloquinolines like 17A --C [28]. The discovery history, SAR studies, X-ray binding and lead-optimization of this series has been the subject of a whole series of recent publications [29][30][31].…”

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

“…Pyrazoloquinoline 74 ( Figure 33 ) has been described as a potent, selective, and orally active phosphodiesterase 10A inhibitor (PDE10A) for the potential treatment of schizophrenia. Compound 74 inhibits MK-801-induced hyperactivity at 3 mg/kg with an ED 50 of 4 mg/kg and exhibits a 6-fold improvement between the ED 50 for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats [ 144 ].…”

A comparative study of binding affinities for 6,7-dimethoxy-4-pyrrolidylquinazolines as phosphodiesterase 10A inhibitors using the linear interaction energy method

“…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][50][51][52][53] which share no structural similarity with the training set that we used for the binding affinity model development [40]. The G obs values span an energy difference of 3.16 kcal/mol (Fig.…”