Abstract:
:Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Charton J,Gauriot M,Totobenazara J,Hennuyer N,Dumont J,Bosc D,Marechal X,Elbakali J,Herledan A,Wen X,Ronco C,Gras-Masse H,Heninot A,Pottiez V,Landry V,Staels B,Liang WG,Leroux F,Tang WJ,Deprez B,Deprez-Poulain Rdoi
10.1016/j.ejmech.2014.12.005subject
Has Abstractpub_date
2015-01-27 00:00:00pages
547-67eissn
0223-5234issn
1768-3254pii
S0223-5234(14)01114-3journal_volume
90pub_type
杂志文章abstract::The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC50 = 19.1 μM) and Fasciola hepatica (IC50 = 17.7 μM), two related parasitic blood and liver flukes responsible for the neglected tropical diseases schistosomiasis and fas...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.04.032
更新日期:2018-05-25 00:00:00
abstract::Herein, we report the synthesis and characterization of new amphiphilic phthalocyanines (Pcs), the study of their singlet oxygen generation capabilities, and biological assays to determine their potential as photosensitizers for photodynamic inactivation of bacteria. In particular, Pcs with an ABAB geometry (where A a...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.111957
更新日期:2020-02-01 00:00:00
abstract::Several diarylamide compounds have been highlighted as potential anticancer agents. Among them, imatinib, dasatinib, and nilotinib have been marketed for treatment of chronic myeloid leukemia (CML). CML is a cancer type that originates in specific cells in bone marrow and is considered as life-threating disease. Imati...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2019.112029
更新日期:2020-02-15 00:00:00
abstract::Persistently activated signal transducer and activator of transcription 3 (STAT3) plays an important role in the development of multiple cancers, and therefore is a potential therapeutic target for cancer prevention. Herein, we report the rational design, synthesis, and biological evaluation of novel potent STAT3 inhi...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112428
更新日期:2020-09-01 00:00:00
abstract::Phosphopantetheine adenylyltransferase (PPAT) is an essential enzyme in Coenzyme A biosynthesis. Because bacterial PPAT and mammalian PPAT are dissimilar, this enzyme is an attractive antibacterial target. Based on the structure of the substrate, 4-phosphopantetheine, a dipeptide library was designed, synthesised and ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(03)00047-3
更新日期:2003-04-01 00:00:00
abstract::The interaction between menin and mixed lineage leukemia (MLL) was identified as an interesting target for treating some cancers including acute leukemia. On the basis of the known crystal structure of the MBM1-menin complex (MBM - menin binding motif), several cyclic peptides were designed. Elaboration of the effecti...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112748
更新日期:2020-12-01 00:00:00
abstract::The present work involves design and synthesis of new substituted 1,4-dihydropyridin-4-yl-phenoxyacetohydrazones (4a-s, 5a-h), starting from 4-hydroxybenzaldehyde. The final compounds were screened for their in vivo anticonvulsant activity by MES, scPTZ and 6 Hz methods, while their anti-inflammatory screening was per...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.10.010
更新日期:2013-01-01 00:00:00
abstract::To evaluate N-hydroxyurea as zinc binding group in the design of MMP inhibitors, two peptidyl 1-hydroxyureas were prepared by N-hydroxycarbamoylation of the diastereomeric dipeptides H-Leu-Phe-NHMe and H-D-Leu-Phe-NHMe. Peptidyl 1-hydroxyureas were more potent than the parent peptides, but dramatically weaker (4-5 ord...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2007.07.002
更新日期:2008-05-01 00:00:00
abstract::Podophyllotoxin (PT) and its clinically used analogues are known to be powerful antitumour agents. These compounds contain a trans fused strained γ-lactone system, a feature that correlates to the process of epimerisation, whereby the trans γ-lactone system of ring D opens and converts to the more thermodynamically st...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.12.037
更新日期:2016-03-03 00:00:00
abstract::Structure-activity relationships for rigid analogues of combretastatin A-4 (CA-4) were investigated, leading to the discovery of a series of 3,4-diaryl-1,2,5-oxadiazole-N-oxides. Among them, 7n' and 7n'' showed remarkable antiproliferative activities against three cancer cell lines in nanomolar concentrations. Interes...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.05.036
更新日期:2019-09-15 00:00:00
abstract::We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV st...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.03.060
更新日期:2018-05-10 00:00:00
abstract::Two potent and selective 5-HT(4) ligands, [(3)H]-5-[(N-propylpiperidin-4-yl)methoxy]-1,2,3,4-tetrahydrobenzo[h][1,6] naphthyridine (1a) and [(3)H]-1-methyl-5-[(N-propylpiperidin-4-yl)methoxy]pyrrolo[1,2-a]thieno[2,3-e]pyrazine (2a) were radiolabelled with tritium. Radioactive labelling was achieved by simultaneous tri...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2009.12.012
更新日期:2010-03-01 00:00:00
abstract::Several new purine nucleosides derivatives of allofuranose were prepared according to Vorbrüggen method, starting from 1,2,5,6-di-O-isopropylidene-α-D-allofuranose and using 1,2,3,5,6-pentaacetoxy-β-D-allofuranose as key intermediate. The synthesized allofuranosyl nucleosides, as well as some acetyl derivatives, were ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.09.046
更新日期:2010-12-01 00:00:00
abstract::Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.10.032
更新日期:2011-01-01 00:00:00
abstract::Pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (7a, PPADS), a nonselective P2X receptor antagonist, was extensively modified to develop more stable, potent, and selective P2X₃ receptor antagonists as potential antinociceptive agents. Based on the results of our previous report, all strong anionic groups in PPADS inc...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.10.026
更新日期:2013-01-01 00:00:00
abstract::A series of 4H-1,2,3-thiadiazolo[5,4-b]indoles were synthesized by novel tandem of oxidative cyclization of 3-alkoxycarbonylhydrazonoindoline-2-thiones, 1,5-H-shift and elimination of tert-butoxy(ethoxy)carbonyl group. The simple method for their modifications by the reactions with electrophilic agents were elaborated...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.11.011
更新日期:2016-01-27 00:00:00
abstract::Several prenylflavonoids have been synthesised and tested against human tumour cell lines. The prenyl unit has been geranyl or a labdane diterpene. These labdane-flavonoids have been synthesised for the first time. The antitumour activity increase with the prenylation at C-8 position. Twenty-three C and O-prenylated a...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.06.025
更新日期:2010-09-01 00:00:00
abstract::Twenty-six naturally occurring oleanolic acid saponins and their derivatives, 16 of which were synthesized in this study, were preliminarily evaluated against human cancer cells. From SAR studies, the presence of α-l-rhamnosyl residue at the terminal of both C-3 and C-28 position for oleanolic acid bidesmosides was im...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.04.016
更新日期:2013-06-01 00:00:00
abstract::We describe the synthesis and characterization of a novel bioconjugate, consisting of an octaarginine cell-penetrating peptide and a highly DNA-affine doxorubicin dimer. The linkage between the two components is composed of a cleavable disulfide bond, which enables the efficient intracellular delivery of the cytotoxic...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2017.02.056
更新日期:2017-04-21 00:00:00
abstract::Heme oxygenase (HO) is a cytoprotective enzyme that can be overexpressed in some pathological conditions, including certain cancers. In this work, novel imidazole derivatives were designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). In these compounds the imidazole ring, cruci...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.04.003
更新日期:2015-01-01 00:00:00
abstract::Polymeric bile acid sequestrants (BAS) have recently attracted much attention as lipid-lowering agents. These non-absorbable materials specifically bind bile acids (BAs) in the intestine, preventing bile acid (BA) reabsorption into the blood through enterohepatic circulation. Therefore, it is important to understand t...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2017.12.015
更新日期:2018-01-20 00:00:00
abstract::Six new bimetallic complexes of the type CuCu, CuCo, CuNi, CuZn and CuMn were prepared. The structures of these complexes and the ligand have been proposed on the basis of FAB mass, elemental analysis, UV-vis, IR, EPR and CV studies. All the complexes completely cleave pBS (SK-) DNA at a concentration of 10 microM; ho...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2005.11.016
更新日期:2006-12-01 00:00:00
abstract::Novel imine derivatives of quinazolin-4(3H)-one were designed and synthesized by using aminoethyl moieties to increase the amine bridge of quinazolin-4(3H)-one amine and then introducing various aromatic aldehydes. The target compounds were characterized by proton nuclear magnetic resonance spectroscopy ((1)H NMR), ca...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.02.053
更新日期:2014-04-22 00:00:00
abstract::Pancreatic cancer is one of the most deadly neoplasm with a 5-year survival rate of less than 6% owing to its remarkable tolerance to nutrient starvation, and new drugs and treatment strategies are urgently needed. During a project aiming at discovery of anticancer agents, we performed a structure modification on poly...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.03.013
更新日期:2019-05-15 00:00:00
abstract::A series of new 1,2-substituted tetrazole derivatives were synthesized and evaluated on MCF-7 (ER positive), MDA-MB-231 and ZR-75 (ER negative) breast cancer cell lines. Out of the fourteen compounds, three compounds 10, 12 and 14 showed higher inhibitory effects on MCF-7 cells. Whereas, compound 8 exhibited higher in...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.11.008
更新日期:2014-01-01 00:00:00
abstract::In this study, two series of coumarin derivatives 5a∼i and 6a∼i were synthesized, and their inhibitory activity against α-glucosidase was determined. The results indicated that most of the synthesized derivatives exhibited prominent inhibitory activities against α-glucosidase. Among them, compounds 5a and 5b showed th...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.112013
更新日期:2020-03-01 00:00:00
abstract::Heterocyclic compounds are the interesting core structures for the development of new bioactive compounds. Fatty acids are derived from renewable raw materials and exhibit various biological activities. Several researchers are amalgamating these two bioactive components to yield bioactive hybrid molecules with some de...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2017.09.069
更新日期:2017-12-01 00:00:00
abstract::The present study aims at design and synthesis of newer gamma-aminobutyric acid (GABA) derivatives with the combination of thiosemicarbazone and GABA pharmacophores in order to develop newer anticonvulsants. The reported compounds were designed as bioisosteric analogues of GABA semicarbazones. The structures of the sy...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2008.01.036
更新日期:2008-12-01 00:00:00
abstract::Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyl...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2006.12.007
更新日期:2007-05-01 00:00:00
abstract::Drug repurposing arises as an interesting alternative to overcome the limited efficacy of current available antibiotics by reducing time, cost and risk associated with drug innovation. In this study, the activity of ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), was evaluated on the control of pre-establis...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.01.046
更新日期:2019-03-15 00:00:00