abstract：:Protein thermal shift assays (TSAs) provide a means for characterizing target engagement through ligand-induced thermal stabilization. Although these assays are widely utilized for screening libraries and validating hits in drug discovery programs, they can impose encumbering operational requirements, such as the avai...

journal_title：ACS medicinal chemistry letters

authors： Dart ML,Machleidt T,Jost E,Schwinn MK,Robers MB,Shi C,Kirkland TA,Killoran MP,Wilkinson JM,Hartnett JR,Zimmerman K,Wood KV

更新日期：2018-04-16 00:00:00

abstract：:A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for their inhibition on six human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms such as the physiologically relevant hCA I, II, VA, VB, VII, and IX and the X-ray complex in adduct with hCA II for some of them investigat...

journal_title：ACS medicinal chemistry letters

authors： Angeli A,di Cesare Mannelli L,Trallori E,Peat TS,Ghelardini C,Carta F,Supuran CT

更新日期：2018-04-09 00:00:00

abstract：:The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cel...

journal_title：ACS medicinal chemistry letters

authors： Yu T,Li N,Wu C,Guan A,Li Y,Peng Z,He M,Li J,Gong Z,Huang L,Gao B,Hao D,Sun J,Pan Y,Shen L,Chan C,Lu X,Yuan H,Li Y,Li J,Chen S

更新日期：2018-02-27 00:00:00

abstract：:The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical ...

journal_title：ACS medicinal chemistry letters

authors： Collibee SE,Bergnes G,Muci A,Browne WF 4th,Garard M,Hinken AC,Russell AJ,Suehiro I,Hartman J,Kawas R,Lu PP,Lee KH,Marquez D,Tomlinson M,Xu D,Kennedy A,Hwee D,Schaletzky J,Leung K,Malik FI,Morgans DJ Jr,Morgan BP

更新日期：2018-02-13 00:00:00

abstract：:Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alky...

journal_title：ACS medicinal chemistry letters

authors： Drakopoulos A,Tzitzoglaki C,McGuire K,Hoffmann A,Konstantinidi A,Kolokouris D,Ma C,Freudenberger K,Hutterer J,Gauglitz G,Wang J,Schmidtke M,Busath DD,Kolocouris A

更新日期：2018-01-29 00:00:00

abstract：:Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting...

journal_title：ACS medicinal chemistry letters

authors： Sammons MF,Kharade SV,Filipski KJ,Boehm M,Smith AC,Shavnya A,Fernando DP,Dowling MS,Carpino PA,Castle NA,Zellmer SG,Antonio BM,Gosset JR,Carlo A,Denton JS

更新日期：2018-01-19 00:00:00

abstract：:Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alt...

journal_title：ACS medicinal chemistry letters

authors： Popovici-Muller J,Lemieux RM,Artin E,Saunders JO,Salituro FG,Travins J,Cianchetta G,Cai Z,Zhou D,Cui D,Chen P,Straley K,Tobin E,Wang F,David MD,Penard-Lacronique V,Quivoron C,Saada V,de Botton S,Gross S,Dang L,Y

更新日期：2018-01-19 00:00:00

abstract：:Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed m...

journal_title：ACS medicinal chemistry letters

authors： Stepan AF,Tran TP,Helal CJ,Brown MS,Chang C,O'Connor RE,De Vivo M,Doran SD,Fisher EL,Jenkinson S,Karanian D,Kormos BL,Sharma R,Walker GS,Wright AS,Yang EX,Brodney MA,Wager TT,Verhoest PR,Obach RS

更新日期：2018-01-04 00:00:00

abstract：:Bacterial resistance has become a worldwide concern after the emergence of metallo-β-lactamases (MBLs). They represent one of the major mechanisms of bacterial resistance against beta-lactam antibiotics. Among MBLs, New Delhi metallo-β-lactamase-1 NDM-1, the most prevalent type, is extremely efficient in inactivating ...

journal_title：ACS medicinal chemistry letters

authors： Spyrakis F,Celenza G,Marcoccia F,Santucci M,Cross S,Bellio P,Cendron L,Perilli M,Tondi D

更新日期：2017-11-26 00:00:00

abstract：:The endogenous amino acid, 5-aminolevulinic acid (5-ALA), has received significant attention as an imaging agent, including ongoing clinical trials for image-guided tumor resection due to its selective uptake and subsequent accumulation of the fluorescent protoporphyrin IX in tumor cells. Based on the widely reported ...

journal_title：ACS medicinal chemistry letters

authors： Pippin AB,Voll RJ,Li Y,Wu H,Mao H,Goodman MM

更新日期：2017-11-15 00:00:00

abstract：:Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral ...

journal_title：ACS medicinal chemistry letters

authors： Bungard CJ,Williams PD,Schulz J,Wiscount CM,Holloway MK,Loughran HM,Manikowski JJ,Su HP,Bennett DJ,Chang L,Chu XJ,Crespo A,Dwyer MP,Keertikar K,Morriello GJ,Stamford AW,Waddell ST,Zhong B,Hu B,Ji T,Diamond TL,Ba

更新日期：2017-11-13 00:00:00

abstract：:The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gr...

journal_title：ACS medicinal chemistry letters

authors： Li Y,Lavey NP,Coker JA,Knobbe JE,Truong DC,Yu H,Lin YS,Nimmo SL,Duerfeldt AS

更新日期：2017-10-19 00:00:00

abstract：:EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functio...

journal_title：ACS medicinal chemistry letters

authors： Sonawane YA,Zhu Y,Garrison JC,Ezell EL,Zahid M,Cheng X,Natarajan A

更新日期：2017-10-02 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

abstract：:The solution behavior of auranofin, Et3PAuCl  and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward re...

journal_title：ACS medicinal chemistry letters

authors： Marzo T,Cirri D,Gabbiani C,Gamberi T,Magherini F,Pratesi A,Guerri A,Biver T,Binacchi F,Stefanini M,Arcangeli A,Messori L

更新日期：2017-09-06 00:00:00

abstract：:Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu...

journal_title：ACS medicinal chemistry letters

authors： Abe M,Seto M,Gogliotti RG,Loch MT,Bollinger KA,Chang S,Engelberg EM,Luscombe VB,Harp JM,Bubser M,Engers DW,Jones CK,Rodriguez AL,Blobaum AL,Conn PJ,Niswender CM,Lindsley CW

更新日期：2017-09-01 00:00:00

abstract：:A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of ...

journal_title：ACS medicinal chemistry letters

authors： Safina BS,Elliott RL,Forrest AK,Heald RA,Murray JM,Nonomiya J,Pang J,Salphati L,Seward EM,Staben ST,Ultsch M,Wei B,Yang W,Sutherlin DP

更新日期：2017-08-25 00:00:00

abstract：:Mitragyna speciosa, also known as kratom, has the potential meet the need for pain medications that lack the addictiveness and overdose risk of classical opioid analgesics, such as morphine. This need is urgent because opioid addiction and overdose deaths have risen throughout diverse segments of U.S. society. Some op...

journal_title：ACS medicinal chemistry letters

authors： Halpenny GM

更新日期：2017-08-08 00:00:00

abstract：:A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interact...

journal_title：ACS medicinal chemistry letters

authors： Millan DS,Kayser-Bricker KJ,Martin MW,Talbot AC,Schiller SER,Herbertz T,Williams GL,Luke GP,Hubbs S,Alvarez Morales MA,Cardillo D,Troccolo P,Mendes RL,McKinnon C

更新日期：2017-07-14 00:00:00

abstract：:The discovery and characterization of two classes of kappa opioid receptor agonists that are biased for G protein over βarrestin signaling are described. ...

journal_title：ACS medicinal chemistry letters

authors： Bohn LM,Aubé J

更新日期：2017-07-05 00:00:00

abstract：:A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racem...

journal_title：ACS medicinal chemistry letters

authors： Bianco G,Meleddu R,Distinto S,Cottiglia F,Gaspari M,Melis C,Corona A,Angius R,Angeli A,Taverna D,Alcaro S,Leitans J,Kazaks A,Tars K,Supuran CT,Maccioni E

更新日期：2017-06-21 00:00:00

abstract：:The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl Δ5,6 tricycle and the 4-oxo Δ5,6 tricycle. The former was elaborated to 4-desmethyl englerin A and the latter served as a common precursor for en...

journal_title：ACS medicinal chemistry letters

authors： Elliott DC,Beutler JA,Parker KA

更新日期：2017-06-06 00:00:00

abstract：:A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed signific...

journal_title：ACS medicinal chemistry letters

authors： Pryde DC,Marron BE,West CW,Reister S,Amato G,Yoger K,Antonio B,Padilla K,Cox PJ,Turner J,Warmus JS,Swain NA,Omoto K,Mahoney JH,Gerlach AC

更新日期：2017-05-18 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：:Water-soluble cyclodextrin (CyD) complexed with porphyrin derivatives with different substituents in the meso-positions showed different photodynamic activities toward cancer cells under illumination at wavelengths over 600 nm, the most suitable wavelengths for photodynamic therapy (PDT). In particular, aniline- and p...

journal_title：ACS medicinal chemistry letters

authors： Ikeda A,Satake S,Mae T,Ueda M,Sugikawa K,Shigeto H,Funabashi H,Kuroda A

更新日期：2017-04-19 00:00:00

abstract：:Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was di...

journal_title：ACS medicinal chemistry letters

authors： Berton P,Di Bona KR,Yancey D,Rizvi SAA,Gray M,Gurau G,Shamshina JL,Rasco JF,Rogers RD

更新日期：2017-04-12 00:00:00

abstract：:Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC50 = 126 nM), was shown to be selective for LOXL2 over LOX and ...

journal_title：ACS medicinal chemistry letters

authors： Hutchinson JH,Rowbottom MW,Lonergan D,Darlington J,Prodanovich P,King CD,Evans JF,Bain G

更新日期：2017-03-01 00:00:00

abstract：:Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, s...

journal_title：ACS medicinal chemistry letters

authors： Daub ME,Prudhomme J,Ben Mamoun C,Le Roch KG,Vanderwal CD

更新日期：2017-02-16 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：:A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N'-end could greatly enhance antiproliferation potency. Among them,...

journal_title：ACS medicinal chemistry letters

authors： Bi C,Zhang N,Yang P,Ye C,Wang Y,Fan T,Shao R,Deng H,Song D

更新日期：2017-01-05 00:00:00

abstract：:Rapid detection and precise evaluation of myocardial viability is necessary to aid in clinical decision making whether to recommend revascularization for patients with myocardial infarction (MI). Three novel 18F-labeled 1-hydroxyanthraquinone derivatives were synthesized, characterized, and evaluated as potential necr...

journal_title：ACS medicinal chemistry letters

authors： Ji AY,Jin QM,Zhang DJ,Zhu H,Su C,Duan XH,Bian L,Sun ZP,Ni YC,Zhang J,Yang Z,Yin ZQ

更新日期：2016-12-28 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：:The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recentl...

journal_title：ACS medicinal chemistry letters

authors： Villemure E,Volgraf M,Jiang Y,Wu G,Ly CQ,Yuen PW,Lu A,Luo X,Liu M,Zhang S,Lupardus PJ,Wallweber HJ,Liederer BM,Deshmukh G,Plise E,Tay S,Wang TM,Hanson JE,Hackos DH,Scearce-Levie K,Schwarz JB,Sellers BD

更新日期：2016-10-31 00:00:00

abstract：:PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining a...

journal_title：ACS medicinal chemistry letters

authors： Yau MK,Liu L,Suen JY,Lim J,Lohman RJ,Jiang Y,Cotterell AJ,Barry GD,Mak JY,Vesey DA,Reid RC,Fairlie DP

更新日期：2016-10-10 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：:Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and h...

journal_title：ACS medicinal chemistry letters

authors： Welsch ME,Zhou J,Gao Y,Yan Y,Porter G,Agnihotri G,Li Y,Lu H,Chen Z,Thomas SB

更新日期：2016-09-17 00:00:00

abstract：:Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, ...

journal_title：ACS medicinal chemistry letters

authors： Cong Y,Wang L,Wang Z,He S,Zhou D,Jing X,Huang Y

更新日期：2016-08-24 00:00:00

abstract：:Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow t...

journal_title：ACS medicinal chemistry letters

authors： Wang Y,Wach JY,Sheehan P,Zhong C,Zhan C,Harris R,Almo SC,Bishop J,Haggarty SJ,Ramek A,Berry KN,O'Herin C,Koehler AN,Hung AW,Young DW

更新日期：2016-07-14 00:00:00

abstract：:Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compo...

journal_title：ACS medicinal chemistry letters

authors： Hoegenauer K,Soldermann N,Stauffer F,Furet P,Graveleau N,Smith AB,Hebach C,Hollingworth GJ,Lewis I,Gutmann S,Rummel G,Knapp M,Wolf RM,Blanz J,Feifel R,Burkhart C,Zécri F

更新日期：2016-06-02 00:00:00

abstract：:ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Zhu Y,Teumelsan N,Walsh SP,Shahripour A,Priest BT,Swensen AM,Felix JP,Brochu RM,Bailey T,Thomas-Fowlkes B,Pai LY,Hampton C,Corona A,Hernandez M,Metzger J,Forrest M,Zhou X,Owens K,Tong V,Parmee E,Roy S,K

更新日期：2016-05-12 00:00:00