Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain

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• 作者：Christa C. Chrovian ; Akinola Soyode-Johnson ; Hong Ao ; Genesis M. Bacani ; Nicholas I. Carruthers ; Brian Lord ; Leslie Nguyen ; Jason C. Rech ; Qi Wang ; Anindya Bhattacharya ; Michael A. Letavic
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：April 20, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：490-497
• 全文大小：430K
• 年卷期：0
• ISSN：1948-7193

文摘

Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC₅₀ = 9 nM; rat P2X7 IC₅₀ = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure–activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included.