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_v3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca_v3.2 currents (>90% inhibition) at 10 μM concentration and exhibited cytotoxic effect (IC₅₀ = 5.9 μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Ca_v3.2 channels.

作为克服铅化合物KYS05090S不良代谢稳定性的生物立体策略，制备了一系列新型的氟代3,4-二氢喹唑啉衍生物，并评估了其对T型钙通道（Ca _v 3.2）的阻滞作用，细胞毒性作用和肝微粒体稳定。其中，含有4-氟苄基酰胺和4-环己基苯环的化合物8h（KCP10068F）在浓度为10μM时能有效阻断Ca _v 3.2电流（抑制率> 90％），并 在A549非小细胞中显示出细胞毒作用（IC ₅₀ = 5.9μM）。与KYS05090S相当的肺癌细胞。再说八小时结果表明，与KYS05090S相比，大鼠和人类肝脏代谢稳定性提高了约2倍。基于这些总体结果，因此8h（KCP10068F）可能是KYS05090S的良好后备化合物，可以作为新型细胞毒剂用于进一步的生物学研究。此外，发现化合物8g（KCP10067F）通过阻断Ca _v 3.2通道部分保护免受炎症性疼痛。