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Kim, Jin Han,Jeong, Hui Rak,Jung, Da Woon,Yoon, Hong Bin,Kim, Sun Young,Kim, Hyoung Ja,Lee, Kyung-Tae,Gadotti, Vinicius M.,Huang, Junting,Zhang, Fang-Xiong,Zamponi, Gerald W.,Lee, Jae Yeol Pergamon 2017 Bioorganic & medicinal chemistry Vol.25 No.17
<P><B>Abstract</B></P> <P>As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Ca<SUB>v</SUB>3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound <B>8h</B> (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca<SUB>v</SUB>3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC<SUB>50</SUB> =5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, <B>8h</B> showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, <B>8h</B> (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound <B>8g</B> (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Ca<SUB>v</SUB>3.2 channels.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>