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 2024-01-20T00:33:15Z 2024-01-20T00:33:15Z 2021-09-05 2017-09-01 0968-0896 https://pubs.kist.re.kr/handle/201004/122309 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(v)3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca(v)3.2 currents (>90% inhibition) at 10 mu M concentration and exhibited cytotoxic effect (IC50 = 5.9 mu M) 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(v)3.2 channels. (C) 2017 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD CALCIUM-CHANNEL BLOCKERS ADENOCARCINOMA A549 CELLS CANCER-CELLS MEDICINAL CHEMISTRY NEUROPATHIC PAIN TUMOR PROLIFERATION STABILITY APOPTOSIS AGENT Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects Article 10.1016/j.bmc.2017.07.010 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.25, no.17, pp.4656 - 4664 BIOORGANIC & MEDICINAL CHEMISTRY 25 17 4656 4664 scie scopus 000407831300012 2-s2.0-85023598088 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article CALCIUM-CHANNEL BLOCKERS ADENOCARCINOMA A549 CELLS CANCER-CELLS MEDICINAL CHEMISTRY NEUROPATHIC PAIN TUMOR PROLIFERATION STABILITY APOPTOSIS AGENT T-type calcium channel 3,4-Dihydroquinazoline Bioisostere Cytotoxic activity Inflammatory pain Liver microsomal stability