Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.

abstract：:By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identifie...

journal_title：ACS medicinal chemistry letters

authors： Bukhtiyarova M,Cook EM,Hancock PJ,Hruza AW,Shaw AW,Adam GC,Barnard RJO,McKenna PM,Holloway MK,Bell IM,Carroll S,Cornella-Taracido I,Cox CD,Kutchukian PS,Powell DA,Strickland C,Trotter BW,Tudor M,Wolkenberg S,Li J,

更新日期：2020-12-23 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：:The polyether ionophore salinomycin has recently gained attention due to its exceptional ability to selectively reduce the proportion of cancer stem cells within a number of cancer cell lines. Efficient single step strategies for the preparation of hydroxamic acid hybrids of this compound varying in N- and O-alkylatio...

journal_title：ACS medicinal chemistry letters

authors： Borgström B,Huang X,Chygorin E,Oredsson S,Strand D

更新日期：2016-04-25 00:00:00

abstract：:[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY...

journal_title：ACS medicinal chemistry letters

authors： Shao X,Carpenter GM,Desmond TJ,Sherman P,Quesada CA,Fawaz M,Brooks AF,Kilbourn MR,Albin RL,Frey KA,Scott PJ

更新日期：2012-09-25 00:00:00

abstract：:A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carbo...

journal_title：ACS medicinal chemistry letters

authors： Pan S,Gray NS,Gao W,Mi Y,Fan Y,Wang X,Tuntland T,Che J,Lefebvre S,Chen Y,Chu A,Hinterding K,Gardin A,End P,Heining P,Bruns C,Cooke NG,Nuesslein-Hildesheim B

更新日期：2013-01-04 00:00:00

abstract：:Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are membrane proteins encoded by four genes (HCN1-4) and widely distributed in the central and peripheral nervous system and in the heart. HCN channels are involved in several physiological functions, including the generation of rhythmic activity, and ...

journal_title：ACS medicinal chemistry letters

authors： Romanelli MN,Del Lungo M,Guandalini L,Zobeiri M,Gyökeres A,Árpádffy-Lovas T,Koncz I,Sartiani L,Bartolucci G,Dei S,Manetti D,Teodori E,Budde T,Cerbai E

更新日期：2019-02-06 00:00:00

abstract：:We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model...

journal_title：ACS medicinal chemistry letters

authors： Chelliah MV,Eagen K,Guo Z,Chackalamannil S,Xia Y,Tsai H,Greenlee WJ,Ahn HS,Kurowski S,Boykow G,Hsieh Y,Chintala M

更新日期：2014-03-11 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：:Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in p...

journal_title：ACS medicinal chemistry letters

authors： Tosh DK,Crane S,Chen Z,Paoletta S,Gao ZG,Gizewski E,Auchampach JA,Salvemini D,Jacobson KA

更新日期：2015-05-20 00:00:00

abstract：:The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substitute...

journal_title：ACS medicinal chemistry letters

authors： Liu J,Yu Y,Kelly J,Sha D,Alhassan AB,Yu W,Maletic MM,Duffy JL,Klein DJ,Holloway MK,Carroll S,Howell BJ,Barnard RJO,Wolkenberg S,Kozlowski JA

更新日期：2020-10-13 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：:A new series of 1,4-naphthoquinones, bearing various cyclic and aliphatic amines on C2, was designed and synthesized to identify antiproliferative agents for triple-negative breast cancer, which represents a clinical challenge without targeted therapies. Among naphthoquinones, 2a and 3a inhibited the proliferation of ...

journal_title：ACS medicinal chemistry letters

authors： Badolato M,Carullo G,Caroleo MC,Cione E,Aiello F,Manetti F

更新日期：2019-02-15 00:00:00

abstract：:The multistep preparation of (11)C-levetiracetam ((11)C-LEV) was carried out by a one-pot radiosynthesis with 8.3 ± 1.6% (n = 8) radiochemical yield in 50 ± 5.0 min. Briefly, the propionaldehyde was converted to propan-1-imine in situ as labeling precursor by incubation with ammonia. Without further separation, the im...

journal_title：ACS medicinal chemistry letters

authors： Cai H,Mangner TJ,Muzik O,Wang MW,Chugani DC,Chugani HT

更新日期：2014-08-19 00:00:00

abstract：:We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray cr...

journal_title：ACS medicinal chemistry letters

authors： Garai S,Raja KS,Papke RL,Deschamps JR,Damaj MI,Thakur GA

更新日期：2018-10-11 00:00:00

abstract：:Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desm...

journal_title：ACS medicinal chemistry letters

authors： Velvadapu V,Glassford I,Lee M,Paul T,Debrosse C,Klepacki D,Small MC,Mackerell AD Jr,Andrade RB

更新日期：2012-03-08 00:00:00

abstract：:Computer-aided drug design could benefit from a greater understanding of how errors arise and propagate in biomolecular modeling. With such knowledge, model predictions could be associated with quantitative estimates of their uncertainty. In addition, novel algorithms could be designed to proactively reduce prediction...

journal_title：ACS medicinal chemistry letters

authors： Faver JC,Ucisik MN,Yang W,Merz KM Jr

更新日期：2013-09-12 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：:We have employed novel fragment-based screening methodology to discover bivalent kinase inhibitors with improved selectivity. Starting from a low molecular weight promiscuous kinase inhibitor, we appended a thiol for subsequent reaction with a library of acrylamide electrophiles. Enzyme-templated screening was perform...

journal_title：ACS medicinal chemistry letters

authors： Kwarcinski FE,Steffey ME,Fox CC,Soellner MB

更新日期：2015-07-13 00:00:00

abstract：:Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionali...

journal_title：ACS medicinal chemistry letters

authors： Koehler MF,Bergeron P,Choo EF,Lau K,Ndubaku C,Dudley D,Gibbons P,Sleebs BE,Rye CS,Nikolakopoulos G,Bui C,Kulasegaram S,Kersten WJ,Smith BJ,Czabotar PE,Colman PM,Huang DC,Baell JB,Watson KG,Hasvold L,Tao ZF,Wang

更新日期：2014-03-21 00:00:00

abstract：:We present the discovery and optimization of a novel series of inhibitors of bacterial UDP-N-acetylglucosamine 2-epimerase (called 2-epimerase in this paper). Starting from virtual screening hits, the activity of various inhibitory molecules was optimized using a combination of structure-based and rational design appr...

journal_title：ACS medicinal chemistry letters

authors： Xu Y,Brenning B,Clifford A,Vollmer D,Bearss J,Jones C,McCarthy V,Shi C,Wolfe B,Aavula B,Warner S,Bearss DJ,McCullar MV,Schuch R,Pelzek A,Bhaskaran SS,Stebbins CE,Goldberg AR,Fischetti VA,Vankayalapati H

更新日期：2013-12-12 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：:This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacologica...

journal_title：ACS medicinal chemistry letters

authors： Jin M,Gokhale PC,Cooke A,Foreman K,Buck E,May EW,Feng L,Bittner MA,Kadalbajoo M,Landfair D,Siu KW,Stolz KM,Werner DS,Laufer RS,Li AH,Dong H,Steinig AG,Kleinberg A,Yao Y,Pachter JA,Wild R,Mulvihill MJ

更新日期：2010-08-30 00:00:00

abstract：:Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysio...

journal_title：ACS medicinal chemistry letters

authors： Liu R,Tzounopoulos T,Wipf P

更新日期：2019-05-08 00:00:00

abstract：:A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain),...

journal_title：ACS medicinal chemistry letters

authors： Mahanti M,Pal KB,Sundin AP,Leffler H,Nilsson UJ

更新日期：2019-12-04 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：: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：: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：: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 atypical chemokine receptor CXCR7 has been studied in various disease settings including immunological diseases and heart disease. Efforts to elucidate the role of CXCR7 have been limited by the lack of suitable chemical tools with a range of pharmacological profiles. A high-throughput screen was conducted to disc...

journal_title：ACS medicinal chemistry letters

authors： Menhaji-Klotz E,Ward J,Brown JA,Loria PM,Tan C,Hesp KD,Riccardi KA,Litchfield J,Boehm M

更新日期：2020-05-14 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