Design, Synthesis And Structure-Activity Relationship Studies Of TASK-3 Modulators And TRPC4 Inhibitors

This thesis consists of two parts, one is about designing, synthesizing and structure-activity relationship studies of TASK-3 modulator, another is about TRPC4 inhibitor.TWIK-related acid-sensitive K+ channels (TASK) are two-pore K+ channels responsible for background or leak K+ current and contribute for setting the resting membrane potential in cells that express them. These channels are expressed in several tissues, mainly in cerebellum and adrenal cortex, and are well known to be overexpressed in cancer cells from breast, ovary and skin. TASK channels are also involved in several activity of central nervous system, aldosterone secretion and cell migration and proliferation, and they could prove to be both a novel tumour marker and a new therapeutic target in cancer.During screening the compounds of our lab, we found compound ZRT435f, which can effectively active TASK-3 channel and application of 10μM ZRT435f led to a pronounced increasing of TASK-3 (CH0-K1 cells) currents (I/I0=3.55±0.47) in 0 mV. Via analyzing ZRT435f s structure, we separated it into four parts, including group A, B, C and phenyl group on the left and designed and synthesized 27 compounds. Compared with ZRT435f, compound C3 showed significantly improved potency (I/I0= 6.37±0.96) and compound B13 (I/I0=0.31±0.07) and B17 (I/I0=0.31±0.04) exhibited good inhibitory activities and they can also change the current characteristic of TASK-3.Transient Receptor Potential Canonical (TRPC) channels are Ca2+-permeable nonselective cation channels distributed widely and involved in diverse physiological functions, such as excitation in neuro and muscle, releasing transmitter, cell proliferation and apoptosis. As an important member of TRPC subfamily, TRPC4 has been widely concerned.Through the cell-based high throughput screening assay, a hit compound ML401 (IC5o=1.05 μM) was discovered. Based on the core structure of ML401, a series of 1-H-benzimidazole-2-amine derivatives were designed and synthesized. Some of the derivatives displayed good inhibitory potency against TRPC4 channels, with the most improved potency achieved by compound 18 (IC50=0.65μM) compared with ML401.