Abstract:
:Activating mutations of REarrange during Transfection (RET) kinase frequently occur in human thyroid and lung cancers. An enormous effort has been devoted to discover potent and selective inhibitors of RET. Selective and potent inhibitors against constitutively active RET mutants are rare to date as identification of selective RET inhibitors is challenging. In a recent effort we identified a novel and specific RET inhibitor of 5-aminopyrazole-4-carboxamide scaffold, which was designed to enhance the metabolic stability of the pyrazolopyrimidine scaffold. In the SAR study described in the current report, we identified the 5-aminopyrazole-4-carboxamide analog 15l, which displays high metabolic stability. Compound 15l is potent against gatekeeper mutant (IC50 = 252 nM) of RET as well as against wild-type RET (IC50 = 44 nM). This substance effectively suppresses growth of Ba/F3 cells transformed with wild-type RET and its gatekeeper mutant (V804M), and thyroid-cancer derived TT cells while it does not affect parental Ba/F3 cells and Nthy ori-3-1, normal thyroid cells. Also, the results of a global kinase profiling assay on a panel of 369 kinases, show that 15l exclusively inhibits RET. Based on its exceptional kinase selectivity, great potency and metabolic stability, 15l represents a promising lead for the discovery of RET directed therapeutic agent and should be a key tool in studies aimed at understanding RET biology.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Yoon H,Shin I,Nam Y,Kim ND,Lee KB,Sim Tdoi
10.1016/j.ejmech.2016.10.050subject
Has Abstractpub_date
2017-01-05 00:00:00pages
1145-1155eissn
0223-5234issn
1768-3254pii
S0223-5234(16)30912-6journal_volume
125pub_type
杂志文章abstract::A comparative study of aryl phosphoramidate and aryl thiophosphoramidate derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) was performed. The study focused on the nature of the substituents and the influence of a thiophosphoramidate in the structure of these derivatives. The rate of alkaline hydrolysis of th...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2004.04.002
更新日期:2004-08-01 00:00:00
abstract::We identified a new series of azole antifungal agents bearing a pyrrolotriazinone scaffold. These compounds exhibited a broad in vitro antifungal activity against pathogenic Candida spp. (fluconazole-susceptible and fluconazole-resistant) and were 10- to 100-fold more active than voriconazole against two Candida albic...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112082
更新日期:2020-03-01 00:00:00
abstract::A series of 16 flavonoids were isolated and prepared from bud exudate of Gardenia urvillei and Gardenia oudiepe, endemic to New Caledonia. Most of them are rare polymethoxylated flavones. Some of these compounds showed noticeable activity against Leishmania (Leishmania) amazonensis, Plasmodium falciparum and Trypanoso...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.01.012
更新日期:2015-03-26 00:00:00
abstract::A series of novel pyridyl acridone derivatives comprised of a pseudo-five-cyclic system to extend the π-conjugated acridone chromophore, were designed and synthesized as potent DNA binding antitumor compounds. Most synthesized compounds displayed good activity against human leukemia K562 cells in MTT tests, with compo...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.02.003
更新日期:2015-03-26 00:00:00
abstract::The synthesis of four new isoxazoline-based amino acids being analogues of previously described glutamate receptor ligands is reported and their affinity for ionotropic glutamate receptors is analyzed in comparison with that of selected model compounds. Molecular modelling investigations have been carried out to ratio...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.12.020
更新日期:2011-02-01 00:00:00
abstract::Antagonists addressing selectively NMDA receptors containing the GluN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2017.12.054
更新日期:2018-01-20 00:00:00
abstract::In the last two decades, trans-sialidase of Trypanosoma cruzi (TcTS) has been an important pharmacological target for developing new anti-Chagas agents. In a continuous effort to discover new potential TcTS inhibitors, 3-amino-3-arylpropionic acid derivatives (series A) and novel phthaloyl derivatives (series B, C and...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.07.005
更新日期:2018-08-05 00:00:00
abstract::Staphylococcus aureus (S. aureus) is responsible for difficult-to-treat and relapsing infections and constitutes one of the most problematic pathogens due to its multiple resistances to clinically available antibiotics. Additionally, the ability of S. aureus to develop small-colony variants is associated with a reduce...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.11.019
更新日期:2014-06-10 00:00:00
abstract::Identifying desired interactions with a target receptor is often the first step when designing new active compounds. However, attention should also be focused on contacts with other proteins that result in either selective or polypharmacological compounds. Here, the search for the structural determinants of selectivit...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.04.010
更新日期:2018-05-10 00:00:00
abstract::Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-m...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.07.044
更新日期:2019-11-01 00:00:00
abstract::The quantitative structure-activity relationships of Plasmodium falciparum and Rat protein farnesyltransferase (PFT) inhibitory activities of 6-cyano-1-(3-methyl-3H-imidazoly-4-ylmethyl)-3-substituted-1,2,3,4-tetrahydroquinoline (THQ) analogues are investigated in order to explore the similarities/deviations between t...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2008.01.025
更新日期:2008-12-01 00:00:00
abstract::Six series of 2-substituted 4-aminobutanamide derivatives were synthesized and evaluated for their ability to inhibit GABA transport proteins mGAT1-4 stably expressed in HEK-293 cell lines. The pIC50 values determined were in the range 4.23-5.23. Two compounds (15b and 15c) were selected for further in vitro studies. ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.06.024
更新日期:2014-08-18 00:00:00
abstract::A facile and efficient approach to the synthesis of prenylated flavonoids as potential chemopreventive agents has been described. This features the synthesis of prenyl halide, prenylation of p-hydroxybenzaldehyde, formation of prenylated polyhydroxychalcone and cyclization of prenylated polyhydroxychalcone to flavanon...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2005.09.008
更新日期:2006-02-01 00:00:00
abstract::The bioactive naphtoquinone lapachol was studied in vitro by a biomimetic model with Jacobsen catalyst (manganese(III) salen) and iodosylbenzene as oxidizing agent. Eleven oxidation derivatives were thus identified and two competitive oxidation pathways postulated. Similar to Mn(III) porphyrins, Jacobsen catalyst main...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2012.06.042
更新日期:2012-08-01 00:00:00
abstract::Molecular hybridization is a ligand based drug design approach is well known recent medicinal chemistry to design anti-parasitic agents. In the present study, we have designed a series of (1-phenyl-9H-pyrido [3,4-b]indol-3-yl) (4-phenylpiperazin-1-yl)methanone derivatives using molecular hybridization approach. Design...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.03.022
更新日期:2018-04-25 00:00:00
abstract::The cholinesterase enzymes play a vital role in maintaining balanced levels of the neurotransmitter acetylcholine in the central nervous system. However, the overexpression of these enzymes results in hampered neurotransmission. Both the major forms of cholinesterase enzymes viz. acetylcholinesterase (AChE) and butyry...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112761
更新日期:2020-12-01 00:00:00
abstract::[1,2,4]Triazolo[1,5-c]pyrimidine is a promising platform to develop adenosine receptor antagonists. Here, we tried to investigate the effect of the substituent at the 8 position of [1,2,4]triazolo[1,5-c]pyrimidine derivatives on affinity and selectivity at the human A3 adenosine receptor subtype. In particular, we hav...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.08.042
更新日期:2018-09-05 00:00:00
abstract::A family of carbonyl-substituted diphenylpyrimidine derivatives (Car-DPPYs) with strong activity against focal adhesion kinase (FAK), were described in this manuscript. Among them, compounds 7a (IC50 = 5.17 nM) and 7f (IC50 = 2.58 nM) displayed equal anti-FAK enzymatic activity to the lead compound TAE226 (6.79 nM). I...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.04.004
更新日期:2019-06-15 00:00:00
abstract::Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhib...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.10.062
更新日期:2014-01-01 00:00:00
abstract::Current healthcare has significantly increased the average life expectancy, leading to a consequently greater incidence of age-related diseases, such as Alzheimer's disease. Following a multitarget approach, in this paper a series of polycyclic maleimide-based derivatives were designed and synthesized aimed at simulta...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.12.003
更新日期:2019-02-01 00:00:00
abstract::Carbazole skeleton is the key structural motif of many biologically active compounds including synthetic and natural products. Over the past several years, a large number of research highlighting the significance of carbazole derivatives has been reported in the literature. The present review focuses on the recent pro...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2015.02.059
更新日期:2015-04-13 00:00:00
abstract::On the basis of computer prediction of biological activity by PASS and toxicity by DEREK, the most promising 32-alkylaminoacyl derivatives of 3-aminobenzo[d]isothiazole were selected for possible local anaesthetic action. This action was evaluated using an in vitro preparation of the isolated sciatic nerve of the rat ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2008.04.006
更新日期:2009-02-01 00:00:00
abstract::In this study, we report the synthesis of novel oxazolidinone derivatives derived from linezolid 3 having p-methoxyphenyl group at C-4 position. In vitro evaluation for their anticancer activity toward cultured A549, DU145, HELA, and MCF7 were carried out. The series of compounds prepared displayed wide range of cytot...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.04.062
更新日期:2014-06-10 00:00:00
abstract::The synthesis and anti-tuberculosis activity for three series of 2,4-disubstituted quinolines is reported. The synthesized compounds were evaluated for activity against M. tuberculosis H37Rv strain; most promising compounds from the series exhibited MIC99 values ranged between 3.125 and 6.25 μg/mL. None of the compoun...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.02.034
更新日期:2015-03-26 00:00:00
abstract::A series of 3-arylidene-5-(4-chloro-phenyl)-2(3H)-furanones (2-13) and their nitrogen analogues 1-benzylpyrrolones (14-18) were synthesized. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. Some of the newly synthesized compounds showed good anti-inflamma...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2008.10.030
更新日期:2009-06-01 00:00:00
abstract::This paper describes the synthesis and characterization of N5-(hetero)arylalkyl-substituted-thiazolo [5,4-d]pyrimidine-5,7-diamine derivatives (4-19) as novel human (h) A2A adenosine receptor (AR) inverse agonists. Competition binding and cyclic AMP assays indicate that the examined compounds behave as hA2A AR inverse...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.06.020
更新日期:2018-07-15 00:00:00
abstract::Two new series of Mannich bases, namely, 1-(morpholino)methyl-3-(4-methylthiobenzyl)-4-(substituted arylidene)amino-1,2,4-triazol-5-thiones 3 and 1-(N-methylpiperazino)methyl-3-(4-methylthiobenzyl)-4-(substituted arylidene)amino-1,2,4-triazol-5-thiones 4 have been synthesized by a three-component Mannich reaction (MCR...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2007.01.015
更新日期:2007-08-01 00:00:00
abstract::A series of 6-acylureido derivatives containing a 3-(pyrrol-2-ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2-one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-1-yl)ethyl)-5-((6-(3-(2-fluoro-4-methoxybe...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.07.108
更新日期:2014-10-06 00:00:00
abstract::The synthesis of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane hydrochloride (D140S.HCl 6), a novel short acting beta(1)-specific adrenoceptor antagonist, has been described. The antagonist potency for D140S.HCl 6 has been compared with esmolol, another short acting agent, ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(02)01399-5
更新日期:2002-09-01 00:00:00
abstract::In this study, we used a solution of FeCl(3) in THF to facilitate the Mannich-type reaction of aldehyde, amine and phosphite compounds to form corresponding alpha-aminophosphonates in a one-pot, three-component reaction. Selected alpha-aminophosphonates were entered into a biological assay test and were studied by doc...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2009.07.009
更新日期:2009-11-01 00:00:00