Discovery of Bivalent Kinase Inhibitors via Enzyme-Templated Fragment Elaboration.

abstract：:Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. ...

journal_title：ACS medicinal chemistry letters

authors： Oehlrich D,Peschiulli A,Tresadern G,Van Gool M,Vega JA,De Lucas AI,Alonso de Diego SA,Prokopcova H,Austin N,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Rombouts FJR,Macdonald G,Moechars D,Gijsen HJM,Trabanco AA

更新日期：2019-07-02 00:00:00

abstract：:A new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than ...

journal_title：ACS medicinal chemistry letters

authors： Darwish A,Blacker M,Janzen N,Rathmann SM,Czorny S,Hillier SM,Joyal JL,Babich JW,Valliant JF

更新日期：2012-02-18 00:00:00

abstract：:An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible rein...

journal_title：ACS medicinal chemistry letters

authors： Liégeois JF,Lespagnard M,Meneses Salas E,Mangin F,Scuvée-Moreau J,Dilly S

更新日期：2014-01-29 00:00:00

abstract：:Despite the perceived stability of the C-F bond, chemical instability and drug-metabolizing enzymes can lead to its cleavage. The resulting release of fluoride and formation of certain metabolites may cause safety issues and warrant the medicinal chemists' attention. ...

journal_title：ACS medicinal chemistry letters

authors： Pan Y

更新日期：2019-06-20 00:00:00

abstract：:(+)- and (-)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant differences in hURAT1 highly expressed HEK293 cell-based inhibition assays, monkey pharma...

journal_title：ACS medicinal chemistry letters

authors： Wang J,Zeng W,Li S,Shen L,Gu Z,Zhang Y,Li J,Chen S,Jia X

更新日期：2017-02-14 00:00:00

abstract：:Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and b...

journal_title：ACS medicinal chemistry letters

authors： Glassford I,Lee M,Wagh B,Velvadapu V,Paul T,Sandelin G,DeBrosse C,Klepacki D,Small MC,MacKerell AD Jr,Andrade RB

更新日期：2014-07-16 00:00:00

abstract：:A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervou...

journal_title：ACS medicinal chemistry letters

authors： Barrow JC,Rittle KE,Reger TS,Yang ZQ,Bondiskey P,McGaughey GB,Bock MG,Hartman GD,Tang C,Ballard J,Kuo Y,Prueksaritanont T,Nuss CE,Doran SM,Fox SV,Garson SL,Kraus RL,Li Y,Marino MJ,Kuzmick Graufelds V,Uebele VN,R

更新日期：2010-02-01 00:00:00

abstract：:Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not ind...

journal_title：ACS medicinal chemistry letters

authors： Garg G,Zhao H,Blagg BS

更新日期：2014-12-12 00:00:00

abstract：:Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed prelimi...

journal_title：ACS medicinal chemistry letters

authors： Guillon R,Pagniez F,Picot C,Hédou D,Tonnerre A,Chosson E,Duflos M,Besson T,Logé C,Le Pape P

更新日期：2013-01-17 00:00:00

abstract：:Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carbox...

journal_title：ACS medicinal chemistry letters

authors： Waterson AG,Kennedy JP,Patrone JD,Pelz NF,Feldkamp MD,Frank AO,Vangamudi B,Souza-Fagundes EM,Rossanese OW,Chazin WJ,Fesik SW

更新日期：2014-11-11 00:00:00

abstract：:With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...

journal_title：ACS medicinal chemistry letters

authors： Huggins WM,Minrovic BM,Corey BW,Jacobs AC,Melander RJ,Sommer RD,Zurawski DV,Melander C

更新日期：2016-11-12 00:00:00

abstract：:Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were selected as putative Notch inhibitors. The evaluation of the antiproliferative effect combined with the inhibition of Notch1 expression in KOPTK1 cell line identified compound 18, featuring a tetrahydronaphthalene-b...

journal_title：ACS medicinal chemistry letters

authors： Quaglio D,Zhdanovskaya N,Tobajas G,Cuartas V,Balducci S,Christodoulou MS,Fabrizi G,Gargantilla M,Priego EM,Carmona Pestaña Á,Passarella D,Screpanti I,Botta B,Palermo R,Mori M,Ghirga F,Pérez-Pérez MJ

更新日期：2019-02-26 00:00:00

abstract：:The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for developme...

journal_title：ACS medicinal chemistry letters

authors： Sromek AW,Si YG,Zhang T,George SR,Seeman P,Neumeyer JL

更新日期：2011-03-10 00:00:00

abstract：:Use of DNA-encoded libraries (DELs) in the pharmaceutical industry has rapidly increased. We discuss what to expect when you run a DEL screen and contemplate guidelines for library design. Additionally, we consider some visionary work and extrapolate to the future. ...

journal_title：ACS medicinal chemistry letters

authors： Satz AL

更新日期：2018-04-17 00:00:00

abstract：:A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4'-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (compo...

journal_title：ACS medicinal chemistry letters

authors： Li J,Wu N,Tian Y,Zhang J,Wu S

更新日期：2013-07-12 00:00:00

abstract：:Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the la...

journal_title：ACS medicinal chemistry letters

authors： Campbell JE,Kuntz KW,Knutson SK,Warholic NM,Keilhack H,Wigle TJ,Raimondi A,Klaus CR,Rioux N,Yokoi A,Kawano S,Minoshima Y,Choi HW,Porter Scott M,Waters NJ,Smith JJ,Chesworth R,Moyer MP,Copeland RA

更新日期：2015-03-04 00:00:00

abstract：:In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular model...

journal_title：ACS medicinal chemistry letters

authors： Wu WL,Hao J,Domalski M,Burnett DA,Pissarnitski D,Zhao Z,Stamford A,Scapin G,Gao YD,Soriano A,Kelly TM,Yao Z,Powles MA,Chen S,Mei H,Hwa J

更新日期：2016-03-12 00:00:00

abstract：:Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with Ki values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl ...

journal_title：ACS medicinal chemistry letters

authors： Latorre A,Schirmeister T,Kesselring J,Jung S,Johé P,Hellmich UA,Heilos A,Engels B,Krauth-Siegel RL,Dirdjaja N,Bou-Iserte L,Rodríguez S,González FV

更新日期：2016-09-21 00:00:00

abstract：:Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation...

journal_title：ACS medicinal chemistry letters

authors： Pettersson M,Johnson DS,Humphrey JM,Butler TW,Am Ende CW,Fish BA,Green ME,Kauffman GW,Mullins PB,O'Donnell CJ,Stepan AF,Stiff CM,Subramanyam C,Tran TP,Vetelino BC,Yang E,Xie L,Bales KR,Pustilnik LR,Steyn SJ,Wood K

更新日期：2015-04-03 00:00:00

abstract：:The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be n...

journal_title：ACS medicinal chemistry letters

authors： Goodwin NC,Cianchetta G,Burgoon HA,Healy J,Mabon R,Strobel ED,Allen J,Wang S,Hamman BD,Rawlins DB

更新日期：2014-08-07 00:00:00

abstract：:A new series of potent TG2 inhibitors are reported that employ a 4-aminopiperidine core bearing an acrylamide warhead. We establish the structure-activity relationship of this new series and report on the transglutaminase selectivity and in vitro ADME properties of selected compounds. We demonstrate that the compounds...

journal_title：ACS medicinal chemistry letters

authors： Prime ME,Brookfield FA,Courtney SM,Gaines S,Marston RW,Ichihara O,Li M,Vaidya D,Williams H,Pedret-Dunn A,Reed L,Schaertl S,Toledo-Sherman L,Beconi M,Macdonald D,Muñoz-Sanjuan I,Dominguez C,Wityak J

更新日期：2012-08-09 00:00:00

abstract：:The phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affin...

journal_title：ACS medicinal chemistry letters

authors： Porter MR,Xiao H,Wang J,Smith SB,Topczewski JJ

更新日期：2019-09-23 00:00:00

abstract：:A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be dis...

journal_title：ACS medicinal chemistry letters

authors： Fu HG,Chen Y,Yu Q,Liu Y

更新日期：2020-05-18 00:00:00

abstract：:The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are p...

journal_title：ACS medicinal chemistry letters

authors： Liu G,Gaines JC,Robbins KJ,Lazo ND

更新日期：2012-08-28 00:00:00

abstract：:A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filg...

journal_title：ACS medicinal chemistry letters

authors： Newton AS,Deiana L,Puleo DE,Cisneros JA,Cutrona KJ,Schlessinger J,Jorgensen WL

更新日期：2017-05-17 00:00:00

abstract：:Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of...

journal_title：ACS medicinal chemistry letters

authors： Johansson NG,Turku A,Vidilaseris K,Dreano L,Khattab A,Ayuso Pérez D,Wilkinson A,Zhang Y,Tamminen M,Grazhdankin E,Kiriazis A,Fishwick CWG,Meri S,Yli-Kauhaluoma J,Goldman A,Boije Af Gennäs G,Xhaard H

更新日期：2020-02-17 00:00:00

abstract：:Tak-242 (resatorvid), a Toll-like Receptor 4 (TLR4) inhibitor, has been identified as a potent suppressor of innate inflammation. As a strategy to target Tak-242 to select tissue, four TLR4-inactive prodrugs were synthesized for activation via two different release mechanisms. Two nitrobenzyl Tak-242 prodrugs released...

journal_title：ACS medicinal chemistry letters

authors： Plunk MA,Alaniz A,Olademehin OP,Ellington TL,Shuford KL,Kane RR

更新日期：2020-01-03 00:00:00

abstract：:A series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against b...

journal_title：ACS medicinal chemistry letters

authors： Wang S,Wang Y,Liu W,Liu N,Zhang Y,Dong G,Liu Y,Li Z,He X,Miao Z,Yao J,Li J,Zhang W,Sheng C

更新日期：2014-02-13 00:00:00

abstract：:In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFRL858R/T790M/C797S. One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFRL858R/T790M/C797S with an IC50 value of 2.2 nM. Cell proliferation assa...

journal_title：ACS medicinal chemistry letters

authors： Li Q,Zhang T,Li S,Tong L,Li J,Su Z,Feng F,Sun D,Tong Y,Wang X,Zhao Z,Zhu L,Ding J,Li H,Xie H,Xu Y

更新日期：2019-05-22 00:00:00

abstract：:Primary open angle glaucoma is the second most common cause of blindness worldwide. Nitric oxide has recently received particular attention as a potential antiglaucoma agent. In this work, gem-dinitroalkyl benzenes are evaluated for their capability to act as a new class of IOP lowering agents. These derivatives have ...

journal_title：ACS medicinal chemistry letters

authors： Blangetti M,Rolando B,Marini E,Chegaev K,Guglielmo S,Lazzarato L,Lucarini L,Masini E,Fruttero R

更新日期：2017-09-13 00:00:00