Novel triazines as potent and selective phosphodiesterase 10A inhibitors
| Autor: | Menelas N. Pangalos, James Joseph Erdei, Rudolf Schindler, Thorsten Hage, Christian Grunwald, Hans Stange, Michael S. Malamas, Julie A. Brennan, Barbara Langen, Nicholas J. Brandon, Norbert Hoefgen, Kristi Fan, Yike Ni, Boyd L. Harrison, Albert J. Robichaud, Karen L. Marquis, Radka Graf, Kevin Parris, Hans-Joachim Lankau, Steven M. Grauer, Rachel Navarra, Ute Egerland, Thomas Kronbach |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Drug
Models Molecular Phosphodiesterase Inhibitors media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Administration Oral Pharmacology Hyperkinesis Crystallography X-Ray Biochemistry Structure-Activity Relationship Pharmacokinetics Drug Discovery Potency Animals Humans Molecular Biology media_common ADME Dose-Response Relationship Drug Molecular Structure Chemistry Phosphoric Diester Hydrolases Triazines Organic Chemistry Phosphodiesterase Bioavailability Rats Molecular Medicine PDE10A Dizocilpine Maleate Selectivity |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(18) |
| ISSN: | 1464-3405 |
| Popis: | 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 (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 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 = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect