Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure.

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：:In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these ...

journal_title：ACS medicinal chemistry letters

authors： Zheng Z,Groaz E,Snoeck R,De Jonghe S,Herdewijn P,Andrei G

更新日期：2020-12-09 00:00:00

abstract：:A series of novel N-acyclic uracil analogs with linear, branched, aromatic, and cyclopropyl-alkynyl as well as heteroaryl moieties at C-5 were prepared using palladium catalyzed Sonogashira and Stille cross-coupling and evaluated against malignant tumor cell lines. C-5-Furan-2-yl uracil derivative 6 was shown to be mo...

journal_title：ACS medicinal chemistry letters

authors： Meščić A,Harej A,Klobučar M,Glavač D,Cetina M,Pavelić SK,Raić-Malić S

更新日期：2015-10-05 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：: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：: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：:We report the synthesis of a novel heat shock protein 90 (hsp90) inhibitor conjugated to a star polymer. Using reversible addition-fragmentation chain-transfer (RAFT) polymerization, we prepared star polymers comprised of PEG attached to a predesigned functional core. The stars were cross-linked using disulfide linker...

journal_title：ACS medicinal chemistry letters

authors： Kim SJ,Ramsey DM,Boyer C,Davis TP,McAlpine SR

更新日期：2013-07-25 00:00:00

abstract：:A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood poo...

journal_title：ACS medicinal chemistry letters

authors： Radeke HS,Purohit A,Harris TD,Hanson K,Jones R,Hu C,Yalamanchili P,Hayes M,Yu M,Guaraldi M,Kagan M,Azure M,Cdebaca M,Robinson S,Casebier D

更新日期：2011-07-22 00:00:00

abstract：:An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-c...

journal_title：ACS medicinal chemistry letters

authors： Schmitz J,Li T,Bartz U,Gütschow M

更新日期：2015-12-28 00:00:00

abstract：:Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound...

journal_title：ACS medicinal chemistry letters

authors： Maurya R,Soni A,Anand D,Ravi M,Raju KS,Taneja I,Naikade NK,Puri SK,Wahajuddin,Kanojiya S,Yadav PP

更新日期：2012-12-11 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：:GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due ...

journal_title：ACS medicinal chemistry letters

authors： Huang H,Meegalla SK,Lanter JC,Winters MP,Zhao S,Littrell J,Qi J,Rady B,Lee PS,Liu J,Martin T,Lam WW,Xu F,Lim HK,Wilde T,Silva J,Otieno M,Pocai A,Player MR

更新日期：2018-12-03 00:00:00

abstract：:CREB (cAMP response element binding protein) has been shown to play an important role in tumor initiation, progression, and metastasis. We discovered that naphthol AS-E, a cell-permeable CREB inhibitor, presented antiproliferative activity in a broad panel of cancer cell lines in vitro. However, it has limited aqueous...

journal_title：ACS medicinal chemistry letters

authors： Li BX,Xie F,Fan Q,Barnhart KM,Moore CE,Rheingold AL,Xiao X

更新日期：2014-08-22 00:00:00

abstract：:Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to fur...

journal_title：ACS medicinal chemistry letters

authors： Zhou Y,Wang Y,Li P,Huang XP,Qi X,Du Y,Huang N

更新日期：2018-10-01 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：:All eight of the major active metabolites of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed...

journal_title：ACS medicinal chemistry letters

authors： Li A,Yuan CC,Chow D,Chen M,Emery MG,Hale C,Zhang X,Subramanian R,St Jean DJ Jr,Komorowski R,Véniant M,Wang M,Fotsch C

更新日期：2011-09-13 00:00:00

abstract：:A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles...

journal_title：ACS medicinal chemistry letters

authors： Jiang Z,Liu X,Yuan Z,He H,Wang J,Zhang X,Gong Z,Hou L,Shen L,Guo F,Zhang J,Wang J,Xu D,Liu Z,Li H,Chen X,Long C,Li J,Chen S

更新日期：2019-06-24 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：:We recently reported a series of 2,6-dipeptidyl-anthraquinone conjugates (AQs) as Trans-Activation Response element (TAR) RNA-binding agents able to inhibit in vitro the HIV-1 nucleocapsid (NC) protein-mediated processes. Because NC is a highly adaptable nucleic acid chaperone assisting several crucial steps along rev...

journal_title：ACS medicinal chemistry letters

authors： Gamba E,Sosic A,Saccone I,Magli E,Frecentese F,Gatto B

更新日期：2020-03-23 00:00:00

abstract：:Two novel benzofuran derivatives coupled with (99m)Tc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, (99m)Tc-BAT-BF showed higher affinity than (99m)Tc-MAMA-BF. In sections of brain tissue from an a...

journal_title：ACS medicinal chemistry letters

authors： Ono M,Fuchi Y,Fuchigami T,Kobashi N,Kimura H,Haratake M,Saji H,Nakayama M

更新日期：2010-08-02 00:00:00

abstract：:Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules...

journal_title：ACS medicinal chemistry letters

authors： Heffron TP,Ndubaku CO,Salphati L,Alicke B,Cheong J,Drobnick J,Edgar K,Gould SE,Lee LB,Lesnick JD,Lewis C,Nonomiya J,Pang J,Plise EG,Sideris S,Wallin J,Wang L,Zhang X,Olivero AG

更新日期：2016-02-16 00:00:00

abstract：:We describe the synthesis and SAR studies of divin-a small molecule that blocks bacterial division by perturbing the assembly of proteins at the site of cell septation. The bacteriostatic mechanism of action of divin is distinct from other reported inhibitors of bacterial cell division and provides an opportunity for ...

journal_title：ACS medicinal chemistry letters

authors： Zhou M,Eun YJ,Guzei IA,Weibel DB

更新日期：2013-09-12 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：: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：:Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in mo...

journal_title：ACS medicinal chemistry letters

authors： Bell IM,Gallicchio SN,Wood MR,Quigley AG,Stump CA,Zartman CB,Fay JF,Li CC,Lynch JJ,Moore EL,Mosser SD,Prueksaritanont T,Regan CP,Roller S,Salvatore CA,Kane SA,Vacca JP,Selnick HG

更新日期：2010-01-12 00:00:00

abstract：:Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was requ...

journal_title：ACS medicinal chemistry letters

authors： Tatani K,Hiratochi M,Nonaka Y,Isaji M,Shuto S

更新日期：2015-01-28 00:00:00

abstract：:Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains el...

journal_title：ACS medicinal chemistry letters

authors： Mpakali A,Saridakis E,Giastas P,Maben Z,Stern LJ,Larhed M,Hallberg M,Stratikos E

更新日期：2020-06-02 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：: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：: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