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Kim, Seon-Mi,Lee, Minhee,Lee, So Young,Lee, Soo-Min,Kim, Eun Jeong,Kim, Jae Sun,Ann, Jihyae,Lee, Jiyoun,Lee, Jeewoo Elsevier 2018 European journal of medicinal chemistry Vol.145 No.-
<P><B>Abstract</B></P> <P>We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the <I>N</I>-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound <B>12c</B> as a highly potent GnRH antagonist with moderate CYP inhibition. Compound <B>12c</B> showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys compared to a known antagonist, Elagolix. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A series of 3-(2-aminoethyl) uracil analogues were synthesized as GnRH antagonists. </LI> <LI> Compound <B>12c</B> showed highly potent GnRH antagonism with moderate CYP inhibition. </LI> <LI> Compound <B>12c</B> exhibited potent and prolonged LH suppression in castrated monkeys. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist
Kim, Seon-Mi,Lee, Minhee,Lee, So Young,Park, Euisun,Lee, Soo-Min,Kim, Eun Jeong,Han, Min Young,Yoo, Taekyung,Ann, Jihyae,Yoon, Suyoung,Lee, Jiyoun,Lee, Jeewoo American Chemical Society 2016 Journal of medicinal chemistry Vol.59 No.19
<P>We developed a compound library for orally available gonadotropin-releasing hormone (GnRH) receptor antagonists that were based on a uracil scaffold. On the basis of in vitro activity and CYP inhibition profile, we selected 18a (SKI2496) for further in vivo studies. Compound 18a exhibited more selective antagonistic activity toward the human GnRH receptors over the GnRHRs in monkeys and rats, and this compound also showed inhibitory effects on GnRH-mediated signaling pathways. Pharmacokinetic and pharmacodynamic evaluations of 18a revealed improved bioavailability and superior gonadotropic suppression activity compared with Elagolix, the most clinically advanced compound. Considering that 18a exhibited highly potent and selective antagonistic activity toward the hGnRHRs along with favorable pharmacokinetic profiles, we believe that 18a may represent a promising candidate for an orally available hormonal therapy.</P>
Lee, Jin Hee,Lee, Yoonji,Ryu, HyungChul,Kang, Dong Wook,Lee, Jeewoo,Lazar, Jozsef,Pearce, Larry V,Pavlyukovets, Vladimir A,Blumberg, Peter M,Choi, Sun ESCOM ; Kluwer Academic Publishers 2011 Journal of computer-aided molecular design Vol.25 No.4
<P>The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.</P>
Physiologically based pharmacokinetic modeling of SNU-0039, an anti-Alzheimer's agent, in rats.
Lee, Kyeong-Ryoon,Chae, Yoon-Jee,Maeng, Han-Joo,Lee, Jeewoo,Kim, Dae-Duk,Chong, Saeho,Shim, Chang-Koo,Chung, Suk-Jae Kluwer Academic/Plenum Publishers 2011 Journal of pharmacokinetics and pharmacodynamics Vol.38 No.5
<P>The objective of this study was to characterize the systemic and tissue kinetics of 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl) benzofuran (SNU-0039), an inhibitor of β-amyloid protein aggregation, in rats. Simultaneous fitting of the data to polyexponential equations indicated that the systemic clearance and steady state volume of distribution were estimated to be 0.0220 l/min/kg and 2.33 l/kg. The clearance and volume of distribution were not dependent on the intravenous dose, in the range from 5 to 20 mg/kg. The tissue (i.e., the brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose tissue) to plasma partition coefficients (K(p)) for SNU-0039 in rats ranged from a low of 0.779 0.314 (muscle) to a high of 5.71 1.66 (liver). The recoveries of DMB were less than 1% of the dose for the renal and biliary excretion, indicative of minor involvements of these pathways in overall elimination. The fraction of bound SNU-0039 to plasma protein was approximately 95.9% and the fraction of SNU-0039 distributed to blood cells was approximately 45.3%. Assuming a flow-limited distribution, the simulated concentration profiles for SNU-0039 in the physiologically based pharmacokinetic model were in reasonable agreement with the observed concentrations in plasma and nine tissues in rats.</P>
Transient receptor potential vanilloid type 1 antagonists: a patent review (2011 - 2014)
Lee, Yoonji,Hong, Sunhye,Cui, Minghua,Sharma, Pankaz K,Lee, Jeewoo,Choi, Sun Informa UK, Ltd. 2015 Expert opinion on therapeutic patents Vol.25 No.3
<P>Introduction: Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel that can be activated by noxious heat, low pH and vanilloid compounds such as capsaicin. Since TRPV1 acts as an integrator of painful stimuli, TRPV1 antagonists can be used as promising therapeutics for new types of analgesics. Areas covered: This review article covers the patents that claim TRPV1 antagonists and were published during 2011 - 2014. The patent evaluation is organized according to the applicant companies, and the representative chemical entities with important in vitro and in vivo data are summarized. Expert opinion: Many pharmaceutical companies showed promising results in the discovery of potent small molecule TRPV1 antagonists, and recently, a number of small molecule TRPV1 antagonists have been advanced into clinical trials. Unfortunately, several candidate molecules showed critical side effects such as hyperthermia and impaired noxious heat sensation in humans, leading to their withdrawal from clinical trials. Some TRPV1 antagonists patented in recent years (2011 - 2014) overcame these undesirable side effects, making the development of TRPV1 antagonists much more promising.</P>
박지우,이상현,이동훈,윤일규,이은주,김은성 순천향대학교 부설 산업기술연구소 2021 순천향 산업기술연구소논문집 Vol.27 No.2
Korean agriculture is currently in a crisis. Because of the problems such as COVID-19, climate change on the Korean Peninsula, declining farm population, and aging people in rural areas, it makes the future of Korean agriculture hopeless. Many studies are being conducted to solve the problem of Korean agriculture, and smart farms based on automation systems are attracting attention as an alternative. If such a control system fails, the entire system becomes inoperable, causing serious problems. This paper implements fault tolerance control systems that enable normal system operation even if such a control system failure occurs. This paper designs a system by selecting a redundancy method with excellent resource efficiency.
Lee, Yeon-Hwa,Song, Na-Young,Suh, Jinyoung,Kim, Do-Hee,Kim, Wonki,Ann, Jihyae,Lee, Jeewoo,Baek, Jeong-Heum,Na, Hye-Kyung,Surh, Young-Joon Elsevier 2018 Cancer letters Vol.431 No.-
<P><B>Abstract</B></P> <P>SIRT1, an NAD<SUP>+</SUP>-dependent histone/protein deacetylase, has diverse physiological actions. Recent studies have demonstrated that SIRT1 is overexpressed in colorectal cancer, suggesting its oncogenic potential. However, the molecular mechanisms by which overexpressed SIRT1 induces the progression of colorectal cancer and its inhibition remain largely unknown. Curcumin (diferuloymethane), a major component of the spice turmeric derived from the plant <I>Curcuma longa</I> L., has been reported to exert chemopreventive and anti-carcinogenic effects on colon carcinogenesis. In the present study, we found that curcumin reduced the expression of SIRT1 protein without influencing its mRNA expression in human colon cancer cells, suggesting posttranslational regulation of SIRT1 by this phytochemical. Notably, ubiquitination and subsequent proteasomal degradation of SIRT1 were induced by curcumin treatment. Results of nano-LC-ESI-MS/MS revealed the direct binding of curcumin to cysteine 67 of SIRT1. In line with this result, the protein stability and clonogenicity of a mutant SIRT1 in which cysteine 67 was substituted by alanine were unaffected by curcumin. Taken together, these observations suggest that curcumin facilitates the proteasomal degradation of oncogenic SIRT1 through covalent modification of SIRT1 at the cysteine 67 residue.</P> <P><B>Highlights</B></P> <P> <UL> <LI> SIRT1 is overexpressed in colorectal cancer tissues compared with normal colon tissues. </LI> <LI> SIRT1 knockdown attenuates viability and migration of human colon cancer cells. </LI> <LI> Silencing of SIRT1 suppressed the growth of HCT-116 derived tumor xenografts. </LI> <LI> Curcumin inhibits migration and growth of HCT-116 cells. </LI> <LI> Curcumin covalently modifies SIRT1 on the cysteine 67 residue, thereby stimulating its proteasomal degradation. </LI> </UL> </P>
Yoon, Suyoung,Kim, Jong Hyun,Koh, Yura,Tran, Phuong-Thao,Ann, Jihyae,Yoon, Ina,Jang, Jayun,Kim, Won Kyung,Lee, Sangkook,Lee, Jiyoun,Kim, Sunghoon,Lee, Jeewoo Elsevier 2017 Bioorganic & medicinal chemistry Vol.25 No.15
<P><B>Abstract</B></P> <P>Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (<B>1</B>) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a <I>N</I>-(3,4-dimethoxybenzyl)benzenesulfonamide (<B>2a</B>) or a <I>N</I>-(2-phenoxyethyl)benzenesulfonamide groups (<B>2b</B>) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers. Among these simplified analogues, compound <B>16</B> and its constrained analogue <B>22</B> effectively inhibited S6K phosphorylation in a dose-dependent manner and exhibited cancer cell specific cytotoxicity against six different types of cancer cells. This result supports that LRS is a viable target for novel anticancer therapy.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Yoon, Suyoung,Kim, Sung-Eun,Kim, Jong Hyun,Yoon, Ina,Tran, Phuong-Thao,Ann, Jihyae,Kim, Changhoon,Byun, Woong Sub,Lee, Sangkook,Kim, Sunghoon,Lee, Jiyoun,Lee, Jeewoo Pergamon 2019 Bioorganic & medicinal chemistry Vol.27 No.6
<P><B>Abstract</B></P> <P>Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>