1156499-86-3Relevant academic research and scientific papers
Highly potent, selective, and orally active phosphodiesterase 10A inhibitors
Malamas, Michael S.,Ni, Yike,Erdei, James,Stange, Hans,Schindler, Rudolf,Lankau, Hans-Joachim,Grunwald, Christian,Fan, Kristi Yi,Parris, Kevin,Langen, Barbara,Egerland, Ute,Hage, Thorsten,Marquis, Karen L.,Grauer, Steve,Brennan, Julie,Navarra, Rachel,Graf, Radka,Harrison, Boyd L.,Robichaud, Albert,Kronbach, Thomas,Pangalos, Menelas N.,Hoefgen, Norbert,Brandon, Nicholas J.
, p. 7621 - 7638 (2012/01/05)
The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
Pyrido[3,2-E]Pyrazines, Process For Preparing The Same, And Their Use As Inhibitors Of Phosphodiesterase 10
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Page/Page column 40, (2009/06/27)
The invention relates to pyrido[3,2-e]pyrazines, to processes for preparing them, to pharmaceutical compositions which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10, as active compounds for treating central nervous system disorders, obesity, and metabolic disorders.
