Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
ACS Chem Neurosci. 2016 Apr 20;7(4):490-7. doi: 10.1021/acschemneuro.5b00303. Epub 2016 Jan 15.
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.
新型 5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪 P2X7 拮抗剂经过优化，可提高血脑屏障通透性，并在大鼠脑中实现高 P2X7 靶点占有率。化合物 25（huP2X7 IC50 = 9 nM；rat P2X7 IC50 = 42 nM）在大鼠中以 10 mg/kg 口服给药时，通过离体放射性配体结合放射自显影技术测量，6 h 时达到 80%的受体占有率。本文描述了该系列化合物的构效关系以及体外 ADME 结果。还包括关键化合物的体内药代动力学数据。
