Publications by authors named "Rudolf Schindler"

The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket.

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Article Synopsis
  • Researchers developed new phenylpyrazine compounds that effectively inhibit the PDE10A enzyme, achieving subnanomolar potency and high selectivity against other PDE family members.
  • They used structure-based drug design to modify the parent compound to enhance its binding affinity and reduce mutagenicity by adding bulky substituents.
  • One potent compound, referred to as 96, showed an impressive IC(50) of 0.7 nM for PDE10A and proved effective in animal models relevant for antipsychotic treatments.
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The in vitro culture behaviour of embryonic stem cells (ESC) is strongly influenced by the culture conditions. Current culture media for expansion of ESC contain some undefined substances. Considering potential clinical translation work with such cells, the use of defined media is desirable.

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Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49.

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