Novel triazines as potent and selective phosphodiesterase 10A inhibitors.

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. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).

Highly potent, selective, and orally active phosphodiesterase 10A inhibitors.

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 IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.

Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors.

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. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.

New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity.

A series of 3- and 5-aryl-1,2,4-oxadiazole derivatives were prepared and tested for anticonvulsant activity in a variety of models. These 1,2,4-oxadiazoles exhibit considerable activity in both pentylenetetrazole (PTZ) and maximal electroshock seizure (MES) models. Compound 10 was protective in the PTZ model in rats with an oral ED(50) of 25.5mg/kg and in the MES model in rats with an oral ED(50) of 14.6mg/kg. Neurotoxicity (rotarod) was observed with an ED(50) of 335mg/kg. We found several oxadiazoles that acted as selective GABA potentiating compounds with no interaction to the benzodiazepine binding site.

Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors.

New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure-activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABAA mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.