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A study on the synthesis of novel hit compound and their evaluation of biological activity against CNS-disoder

초록/요약 도움말

Synthesis and biological evaluation as T-type calcium channel blockers Voltage-dependent calcium channels are the main pathway for calcium ion influx to the cellular membrane. The mechanism invoves the difference in membrane potential, and this plays an important physiological role in the excitability cells. Based on electrophysiological and pharmacological characteristics, voltage-dependent calcium channels are classified as either high-voltage-activated (L, N, P, Q/R type) channels or low-voltage-activated (T-type) channels. Selective T-type calcium channel blockers may have high potentials for the treatment of some types of cancer, hypertension, cardiac arrhythmia, and CNS-related disorders such as epilepsy, neurophatic pain and insomnia. Mibefradil, the first marketed selective T-type calcium channel blocker, was withdrawn from the market due to its drug-drug interaction. Unfortunately, there are no potent and selective T-type calcium channel blockers which are available for clinical use until now. Three series of compounds were designed as T-type calcium channel blockers via lignad based drug design (LBDD) system. To optimize the suggest structure, over 150 derivatives were synthesized and their inhibitory activities on T-type calcium channel were evaluated by in vitro activities using the FDSS6000 HTS system and patch clamp method. As a result, many of the compounds showed better potency than intial hit compounds as well as they exhibited similar activity compared to mibefradil. Especially compound 4k of Type I showed better IC50 value than inhital hit compound (A) and mibefradil.

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초록/요약 도움말

Study on synthesis and biological activities of hit compound for depression TREK-1 channel, one of the subfamily of mechano-gated potassium channels, consists of four transmembrane segments and two pore-forming domains. These channels are opened by stretch, heat, intracellular acidosis, depolarization, lipids and volatile general anesthetics. Moreover, human TREK-1 channels are widely expressed in the CNS neurons, prefrontal cortex, hippocampus, hypothalamus and peripheral tissues. Recent in vivo studies reveal that TREK-1 channels have an important role in clinical depression. In addition, the correlation between TREK-1 and T-type calcium channels is reported. Therefore, the small molecular libraries which were synthesized for T-type calcium channel blocker were evaluated by %inhibitory activities for TREK-1 channel blocker. A series of 1-(2-hydroxy-3-phenoxypropyl)piperidine was modified from compounds 11a and they showed good inhibitory activities against TREK-1 channels. Compounds 28d, 28o, 28n, and 28r exhibited better potency %inhibitory activities. Moreover, they showed good off-target activities between TREK-1 channels and T-type calcium channels. Thus, the selected compounds which showed good activities in the in vitro assay were tested for metabolic stability such as microsomal stability and CYP 450 test before in vivo assay to figure out stability of the compounds. Compounds 28o, 28q, and 28r showed similar activities with fluoxetine known as antidepressant in 50 mg dose. Among them, 28r were subjected to the measurement of pharmacokinetic profiles because of its excellent efficacy. This series of compounds showed promising preliminary activities as TREK-1channel blockers.

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초록/요약 도움말

Design, synthesis and biological evaluation of triple reuptake inhibitors for major depression Monoamines such as dopamine (DA), serotonin (5-HT) and norepinephrine (NE) have an important modulating role in neurotransmission and are deeply associated with a variety of physiological functions and pathological conditions. Even with the development of several selective monoamine transporter inhibitors to treat a number of psychological and neurological disorders, important issues regarding the selectivity and mechanisms of action of these drugs are still uncertain. The established treatments like selective serotonin reuptake inhibitor (SSRI) and serotonin and noepinephrine reuptake inhibitor (SNRI) have some disadvantages such as low efficacy and low expression. To circumvenet this problem, one strategy is to develop a triple (DA, 5-HT and NE) reuptake inhibitor to reduce the therapeutic lag and improve its efficacy as a treatment for depression. Our initial approach began with a pharmacophore built-up with structure of leading candidate for depression with triple reuptake inhibition as a mode of action. With efforts toward a novel triple reuptake inhibitor for depression, three types of moieties were found as initial hit compounds with nanomolar activity in binding and reuptake inhibition. In Type II, most of these compounds showed better potency for NET and DAT than potency for SERT. Compounds 38a and 38b exhibited nanomolar activity in binding and reuptake inhibition. Moreover, Type III surprisingly increased potency at SERT than Type I and Type II. Among these series, 43a, 43d and 43h showed excellent inhibitory activities as triple reuptake inhibitors.

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초록/요약 도움말

Discovery of mitchondrial dysfunction modulators for Alzheimer’s disease Alzheimer’s disease (AD), type of dementia, is a typical degenerative brain disease in the aged population clinically characterized by progressive intellectual deterioration. The onset age of this disease usually at the age of 36 to 45 years, and finds more than 10% of people at the age of 65. In the age of 85, more than 25% of the populations suffer from this disease. The biggest risk factor for the disease is increasing age, but family history and genetics are also important. Although the etiology of AD is unknown, recent reports show that mitochondrial permeability transition pore (mPTP) is involved in mitochondrial dysfunction induced byamyloid beta toxicity. This study was proceeded to discover hit compounds of mitochondrial dysfunction modulators for Alzheimer’s disease. Overall 216 compounds were evaluated for various biological activities of mPTP blockers. The compounds were designed based on the benzolactam derivatives of Type I using TSPO ligand and urea derivatives of Type II using Cyp-A inhibitor. Many compounds in the two series (Type I and Type II) showed good potency in JC-1 assay. Through five assay methods, four hit compounds (51af, 51ap, 52aa, 52ak) were found as mPTP blocker for mitochondrial dysfunction modulators. Based on the result of this study, structural optimization will be followed with this scaffold to find a lead compound of mPTP opening blockers for Alzheimer’s disease.

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