化学
自交轴蛋白
四唑
系列(地层学)
药理学
立体化学
生物化学
受体
医学
生物
古生物学
溶血磷脂酸
作者
Christopher G. Thomson,Darren Le Grand,Mark R. Dowling,David T. Beattie,Lucy M. Elphick,Michael Faller,Mark Freeman,Elizabeth Hardaker,Victoria Head,R. Hemmig,Johan C. Hill,Andrew Lister,David D. Pascoe,S. Rieffel,BP Shrestha,Oliver Steward,F. Zink
标识
DOI:10.1016/j.bmcl.2020.127663
摘要
A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments.
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