Discovery of a novel broad-spectrum antifungal agent derived from albaconazole.

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：:An original design and synthesis of fluorescent ligands for melatonin receptor studies is presented and consists in the fusion of the endogenous ligand with the fluorescent BODIPY core. Probes I-IV show high affinities for MT1 and MT2 melatonin receptors and exhibit fluorescence properties compatible with cell observa...

journal_title：ACS medicinal chemistry letters

authors： Thireau J,Marteaux J,Delagrange P,Lefoulon F,Dufourny L,Guillaumet G,Suzenet F

更新日期：2013-11-20 00:00:00

abstract：:A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with ...

journal_title：ACS medicinal chemistry letters

authors： Dvorak CA,Coate H,Nepomuceno D,Wennerholm M,Kuei C,Lord B,Woody D,Bonaventure P,Liu C,Lovenberg T,Carruthers NI

更新日期：2015-07-20 00:00:00

abstract：:Collaborations between the pharmaceutical industry and contract research organizations continue to represent an attractive alternative to internal drug discovery within a single organization. This Viewpoint covers many of the business models and strategies that are employed in industry-contract research organization c...

journal_title：ACS medicinal chemistry letters

authors： Steadman VA

更新日期：2018-06-04 00:00:00

abstract：:The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TD...

journal_title：ACS medicinal chemistry letters

authors： Laulumaa S,Hansen KV,Masternak M,Drapier T,Francotte P,Pirotte B,Frydenvang K,Kastrup JS

更新日期：2018-11-04 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：:Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFD-motif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which resi...

journal_title：ACS medicinal chemistry letters

authors： Hou J,Teo T,Sykes MJ,Wang S

更新日期：2013-06-24 00:00:00

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：: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：:The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a p...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Walsh SP,Yan Y,de Jesus RK,Shahripour A,Teumelsan N,Zhu Y,Ha S,Owens KA,Thomas-Fowlkes BS,Felix JP,Liu J,Kohler M,Priest BT,Bailey T,Brochu R,Alonso-Galicia M,Kaczorowski GJ,Roy S,Yang L,Mills SG,Garcia M

更新日期：2012-03-28 00:00:00

abstract：:A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 μM) than the parent drug TFV. The most active compound 11 (IC50: 0.71 μM), a bis(l-valine) ester pr...

journal_title：ACS medicinal chemistry letters

authors： Wang A,Wu S,Tao Z,Li X,Lv K,Ma C,Li Y,Li L,Liu M

更新日期：2019-05-16 00:00:00

abstract：:In this study the μ opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH2) and Dmt1-DALDA (Dmt-d-Arg-Phe-Lys-NH2, Dmt = 2',6'-dimethyltyrosine) were glycosylated at the N- or C-terminus. Subsequently, the modified peptides were subjected to in vitro and in vivo evaluation. In contrast to the N-terminally modified...

journal_title：ACS medicinal chemistry letters

authors： Ballet S,Betti C,Novoa A,Tömböly C,Nielsen CU,Helms HC,Lesniak A,Kleczkowska P,Chung NN,Lipkowski AW,Brodin B,Tourwé D,Schiller PW

更新日期：2014-04-10 00:00:00

abstract：:Approximately 1.7 million Americans develop hospital associated infections each year, resulting in more than 98,000 deaths. One of the main contributors to such infections is the Gram-negative pathogen Acinetobacter baumannii. Recently, it was reported that aryl 2-aminoimidazole (2-AI) compounds potentiate macrolide a...

journal_title：ACS medicinal chemistry letters

authors： Hubble VB,Bartholomew KR,Weig AW,Brackett SM,Barlock SL,Mattingly AE,Nemeth AM,Melander RJ,Melander C

更新日期：2020-08-12 00:00:00

abstract：:PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, and Boehringer Ingelheim, etc.), and biotechnology ...

journal_title：ACS medicinal chemistry letters

authors： Gao H,Sun X,Rao Y

更新日期：2020-03-12 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：:Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinson's and Alzheimer's. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this clas...

journal_title：ACS medicinal chemistry letters

authors： Li Y,Ganesh T,Diebold BA,Zhu Y,McCoy JW,Smith SM,Sun A,Lambeth JD

更新日期：2015-08-31 00:00:00

abstract：:The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (tw...

journal_title：ACS medicinal chemistry letters

authors： Praveen P,Tailhades J,Rosengren KJ,Liu M,Wade JD,Bathgate RAD,Hossain MA

更新日期：2020-10-22 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：:Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel f...

journal_title：ACS medicinal chemistry letters

authors： Paulson CN,Guan X,Ayoub AM,Chan A,Karim RM,Pomerantz WCK,Schönbrunn E,Georg GI,Hawkinson JE

更新日期：2018-10-31 00:00:00

abstract：:A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cru...

journal_title：ACS medicinal chemistry letters

authors： Jones BD,Tochowicz A,Tang Y,Cameron MD,McCall LI,Hirata K,Siqueira-Neto JL,Reed SL,McKerrow JH,Roush WR

更新日期：2015-12-15 00:00:00

abstract：:Although heparan sulfate (HS) has been implicated in facilitating entry of enveloped viruses including herpes simplex virus (HSV), small molecules that effectively compete with this abundant, cell surface macromolecule remain unknown. We reasoned that entry of HSV-1 involving its glycoprotein D (gD) binding to HS coul...

journal_title：ACS medicinal chemistry letters

authors： Gangji RN,Sankaranarayanan NV,Elste J,Al-Horani RA,Afosah DK,Joshi R,Tiwari V,Desai UR

更新日期：2018-07-16 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：: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：:A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating...

journal_title：ACS medicinal chemistry letters

authors： Stucchi M,Gmeiner P,Huebner H,Rainoldi G,Sacchetti A,Silvani A,Lesma G

更新日期：2015-06-23 00:00:00

abstract：:Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structu...

journal_title：ACS medicinal chemistry letters

authors： Wills TJ,Lipkus AH

更新日期：2020-09-10 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：:SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism dire...

journal_title：ACS medicinal chemistry letters

authors： Rydberg P,Gloriam DE,Zaretzki J,Breneman C,Olsen L

更新日期：2010-03-15 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：:A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key str...

journal_title：ACS medicinal chemistry letters

authors： Dubernet M,Duguet N,Colliandre L,Berini C,Helleboid S,Bourotte M,Daillet M,Maingot L,Daix S,Delhomel JF,Morin-Allory L,Routier S,Walczak R

更新日期：2013-04-10 00:00:00

abstract：:Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonis...

journal_title：ACS medicinal chemistry letters

authors： Pasquinucci L,Parenti C,Ruiz-Cantero MC,Georgoussi Z,Pallaki P,Cobos EJ,Amata E,Marrazzo A,Prezzavento O,Arena E,Dichiara M,Salerno L,Turnaturi R

更新日期：2020-01-28 00:00:00