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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>
Study on Dynamic Bond-Slip Constitutive Relation of Corroded Mortar Anchor
Haitao Wang,Yue Xin,Pengbo Zhang,Minghua Cui 대한토목학회 2021 KSCE JOURNAL OF CIVIL ENGINEERING Vol.25 No.12
In order to study the bonding performance of corroded mortar anchor under dynamic load and reveal the mechanism of dynamic bond-slip, dynamic pull-out tests for mortar anchors with different corrosion degrees were carried out. On the basis of the average bond stress and relative slip, the basic bond-slip constitutive relation of corroded mortar anchor was established according to the measured data. The bond stress under different loading frequency were fitted, and the dynamic influence coefficient affecting the bond performance of mortar anchor was obtained. Based on the bond stress-slip relationship of each point in the anchorage section under different corrosion degrees, the position function in anchorage section was deduced. According to the above basic bond-slip relation, dynamic influence coefficient and anchorage position function, the dynamic bond-slip constitutive relation of corroded mortar anchor regarding to anchorage position was established, which could provide reference for the study on the durability of mortar anchor and its dynamic anchorage performance.
Hoang, Van-Hai,Ngo, Van T. H.,Cui, Minghua,Manh, Nguyen Van,Tran, Phuong-Thao,Ann, Jihyae,Ha, Hee-Jin,Kim, Hee,Choi, Kwanghyun,Kim, Young-Ho,Chang, Hyerim,Macalino, Stephani Joy Y.,Lee, Jiyoun,Choi, S American Chemical Society 2019 Journal of medicinal chemistry Vol.62 No.17
<P>Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor <B>1</B>, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.</P> [FIG OMISSION]</BR>
Hoang, Van-Hai,Tran, Phuong-Thao,Cui, Minghua,Ngo, Van T. H.,Ann, Jihyae,Park, Jongmi,Lee, Jiyoun,Choi, Kwanghyun,Cho, Hanyang,Kim, Hee,Ha, Hee-Jin,Hong, Hyun-Seok,Choi, Sun,Kim, Young-Ho,Lee, Jeewoo American Chemical Society 2017 Journal of medicinal chemistry Vol.60 No.6
<P>Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of beta-amyloid peptides (pGlu-A beta) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, A beta 3E-42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform A beta and total A beta and restored cognitive functions. This potent A beta-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong-interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.</P>
Inhibitory effect of tartrate against phosphate-induced DJ-1 aggregation
Kim, Min Soo,Lee, Sangmin,Yun, Sanguk,Suh, Pann-Ghill,Park, Jongmi,Cui, Minghua,Choi, Sun,Cha, Sun-Shin,Jin, Wook Elsevier 2018 INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES Vol.107 No.2
<P><B>Abstract</B></P> <P>The DJ-1 protein engages in diverse cellular and pathological processes, including tumorigenesis, apoptosis, sperm fertilization, and the progression of Parkinson’s disease (PD). The functional dimeric form of DJ-1 transforms into non-functional filamentous aggregates in an inorganic phosphate (P<SUB>i</SUB>)-dependent manner in vitro. Here, we demonstrated that P<SUB>i</SUB> and reactive oxygen species (ROS) induce DJ-1 aggregation in Neuro2A and SH-SY5Y cells. Remarkably, tartrate treatment significantly reduced P<SUB>i</SUB>- and ROS-induced DJ-1 aggregation and restored P<SUB>i</SUB>- and ROS-provoked cell death using quantitative data as mean±standard deviation, and statistics. Mechanistically, tartrate prevented DJ-1 aggregation via occupying the P<SUB>i</SUB>-binding site. These findings revealed an unexpected physiological role of tartrate in the maintenance of DJ-1 function, and thus, a potential use as an inhibitor of DJ-1 aggregation.</P>
Shyam Kumar Mallik,Hak Sung Kim,Da Yu Li,Minghua Cui,송현옥,박현 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.3
Malarial calpain is a cysteine protease believed to be a central mediator essential for parasitic activities. N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN), a calpain inhibitor, showed an excellent inhibitory effect on the erythrocytic stages of Plasmodium falciparum. However the aldehyde group of ALLN makes it susceptible to metabolism. Therefore, we designed α,β-unsaturated carbonyl peptides that could serve as electrophiles for cysteine residues in calpain. Among the synthetic analogs based on the structure of ALLN, peptidyl esters 7, 8 and 9 showed the most potent anti-malarial effects, with the same IC50 values of 5.0 μM. Also they showed the high selective toxicity for the malaria versus Hela cell with 40.6, 69.2 and 24.3 fold for 7, 8 and 9, respectively. Dipeptidyl α,β-unsaturated carbonyl derivatives consisting of two amino acids gave better anti-malarial effects than those consisting with one amino acid. The fluctuation in anti-malarial activity with small changes in chemical structure indicates the possibilities of improving synthetic analogs.
Ngo, Van T.H.,Hoang, Van-Hai,Tran, Phuong-Thao,Ann, Jihyae,Cui, Minghua,Park, Gyungseo,Choi, Sun,Lee, Jiyoun,Kim, Hee,Ha, Hee-Jin,Choi, Kwanghyun,Kim, Young-Ho,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.5
<P><B>Abstract</B></P> <P>Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer’s disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound <B>202</B> as a potential candidate because it forms an additional hydrophobic interaction in the <I>h</I>QC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATcl expression
( Ju Hee Kang ),( Zheng Ting ),( Mi Ran Moon ),( Jung Seon Sim ),( Jung Min Lee ),( Kyung Eun Doh ),( Sunhye Hong ),( Minghua Cui ),( Sun Choi ),( Hyeun Wook Chang ),( Hea Young Park Choo ),( Mijung Y 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibi-tors having a benzoxazole scaffold as a potential anti-osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound. K7, inhibited the bone resorptive activity of osteoclasts. The anti-osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1. an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK. as well as NF-KB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo. corroborating the in vitro data. Thus, IG exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption.
Manganese-cobalt hexacyanoferrate cathodes for sodium-ion batteries
Pasta, Mauro,Wang, Richard Y.,Ruffo, Riccardo,Qiao, Ruimin,Lee, Hyun-Wook,Shyam, Badri,Guo, Minghua,Wang, Yayu,Wray, L. Andrew,Yang, Wanli,Toney, Michael F.,Cui, Yi The Royal Society of Chemistry 2016 Journal of materials chemistry. A, Materials for e Vol.4 No.11
<P>Prussian Blue analogues (PBAs) have shown promise as electrode materials for grid-scale batteries because of their high cycle life and rapid kinetics in aqueous-based electrolytes. However, these materials suffer from relatively low specific capacity, which may limit their practical applications. Here, we investigate strategies to improve the specific capacity of these materials while maintaining their cycling stability and elucidate mechanisms that enhance their electrochemical properties. In particular, we have studied the electrochemical and structural properties of manganese hexacyanoferrate (MnHCFe) and cobalt hexacyanoferrate (CoHCFe) in an aqueous, sodium-ion electrolyte. We also studied manganese-cobalt hexacyanoferrate (Mn-CoHCFe) solid solutions with different Mn/Co ratios that combine properties of both MnHCFe and CoHCFe. The materials have the characteristic open-framework crystal structure of PBAs, and their specific capacities can be significantly improved by electrochemically cycling (oxidizing and reducing) both the carbon-coordinated Fe and the nitrogen-coordinated Co or Mn ions.<I>In situ</I>synchrotron X-ray diffraction studies and<I>ex situ</I>soft X-ray absorption spectroscopy combined with an in-depth electrochemical characterization provide insight into the different electrochemical properties associated with the Fe, Co, and Mn redox couples. We show that cycling the C-coordinated Fe preserves the crystal structure and enables the outstanding kinetics and cycle life previously displayed by PBAs in aqueous electrolytes. On the other hand, the N-coordinated Co and Mn ions exhibit a slower kinetic regime due to structural distortions resulting from the weak N-coordinated crystal field, but they still contribute significantly towards increasing the specific capacity of the materials. These results provide the understanding needed to drive future development of PBAs for grid-scale applications that require extremely high cycle life and kinetics.</P>
Ngo, Van T.H.,Hoang, Van-Hai,Tran, Phuong-Thao,Van Manh, Nguyen,Ann, Jihyae,Kim, Eunhye,Cui, Minghua,Choi, Sun,Lee, Jiyoun,Kim, Hee,Ha, Hee-Jin,Choi, Kwanghyun,Kim, Young-Ho,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.12
<P><B>Abstract</B></P> <P>Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer’s disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC<SUB>50</SUB> values in a low nanomolar range, and were further studied for <I>in vitro</I> toxicity and <I>in vivo</I> activity. Among these, inhibitors <B>51</B> and <B>53</B> displayed the most potent Aβ<SUB>N3pE−40</SUB>-lowering effects in <I>in vivo</I> acute model with reasonable BBB penetration, without showing cytotoxicity and <I>h</I>ERG inhibition. The molecular modeling analysis of <B>53</B> indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound <B>53</B> may serve as a potential candidate for anti-Alzheimer’s agents.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>