Novel triazines as potent and selective phosphodiesterase 10A inhibitors

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• 作者：Michael S. Malamas ; Hans Stange ; Rudolf Schindler ; Hans-Joachim Lankau ; Christian Grunwald ; Barbara Langen ; Ute Egerl ; Thorsten Hage ; Yike Ni ; James Erdei ; Kristi Yi Fan ; Kevin Parris ; Karen L. Marquis ; Steve Grauer ; Julie Brennan ; Rachel Navarra ; Radka Graf ; Boyd L. Harrison ; Albert Robichaud ; Thomas Kronbach ; et al.
• 关键词：PDE10A ; phosphodiesterase 10A ; cAMP ; cyclic adenosine monophosphate ; cGMP ; cyclic guanine monophosphate ; MSN ; medium spiny neuron ; MK-801 ; dizocilpine maleate ; MED ; minimal effective dose ; PDE ; cyclic nucleotide phosphodiesterase ; LMA ; locomotor activity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 September, 2012
• 年：2012
• 卷：22
• 期：18
• 页码：5876-5884
• 全文大小：1261 K

文摘

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 lass=""boldFont"">66 was highly potent for PDE10A (IC₅₀ = 1.4 nM), demonstrated high selectivity (>200¡Á) 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).