1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain.

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：: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：:A series of alkylpyrimidine-4,6-diol derivatives were designed and synthesized as novel GRP84 agonists based on a high-throughput screening (HTS) hit 1. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. These novel GPR84 agonists will provide valuabl...

journal_title：ACS medicinal chemistry letters

authors： Liu Y,Zhang Q,Chen LH,Yang H,Lu W,Xie X,Nan FJ

更新日期：2016-03-30 00:00:00

abstract：:To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists ...

journal_title：ACS medicinal chemistry letters

authors： Ogawa S,Watanabe T,Sugimoto I,Moriyuki K,Goto Y,Yamane S,Watanabe A,Tsuboi K,Kinoshita A,Kigoshi H,Tani K,Maruyama T

更新日期：2016-01-04 00:00:00

abstract：:DNA methylation is known as the prima donna epigenetic mark for its critical role in regulating local gene transcription. Changes in the landscape of DNA methylation across the genome occur during cellular transition, such as differentiation and altered neuronal plasticity, and become dysregulated in disease states su...

journal_title：ACS medicinal chemistry letters

authors： Chua GNL,Wassarman KL,Sun H,Alp JA,Jarczyk EI,Kuzio NJ,Bennett MJ,Malachowsky BG,Kruse M,Kennedy AJ

更新日期：2019-01-31 00:00:00

abstract：:Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and to...

journal_title：ACS medicinal chemistry letters

authors： Rabea SM,Baradaran-Heravi A,Balgi AD,Krause A,Hosseini Farahabadi S,Roberge M,Grierson DS

更新日期：2019-04-09 00:00:00

abstract：:S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal ...

journal_title：ACS medicinal chemistry letters

authors： Sun X,Wasley JW,Qiu J,Blonder JP,Stout AM,Green LS,Strong SA,Colagiovanni DB,Richards JP,Mutka SC,Chun L,Rosenthal GJ

更新日期：2011-03-11 00:00:00

abstract：:mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified α-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation β-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. S...

journal_title：ACS medicinal chemistry letters

authors： He R,Yu ZH,Zhang RY,Wu L,Gunawan AM,Zhang ZY

更新日期：2015-11-03 00:00:00

abstract：:Medicinal chemists have increasing opportunities to transition from the pharmaceutical industry to academic medical centers interested in translational research. This Viewpoint highlights some of the differences between these two cultures and strategies to succeed in academic drug discovery. ...

journal_title：ACS medicinal chemistry letters

authors： Barrow JC

更新日期：2019-04-15 00:00:00

abstract：:Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while sev...

journal_title：ACS medicinal chemistry letters

authors： Brincat JP,Broccatelli F,Sabatini S,Frosini M,Neri A,Kaatz GW,Cruciani G,Carosati E

更新日期：2012-01-23 00:00:00

abstract：:The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known pip...

journal_title：ACS medicinal chemistry letters

authors： Nakajima R,Oono H,Sugiyama S,Matsueda Y,Ida T,Kakuda S,Hirata J,Baba A,Makino A,Matsuyama R,White RD,Wurz RΡ,Shin Y,Min X,Guzman-Perez A,Wang Z,Symons A,Singh SK,Mothe SR,Belyakov S,Chakrabarti A,Shuto S

更新日期：2020-02-27 00:00:00

abstract：:With the COVID-19 pandemic, the evolutionary fate of SARS-CoV-2 becomes a matter of utmost concern. Mutation D614G in the spike (S) protein has become dominant, and recent evidence suggests it yields a more stable phenotype with higher transmission efficacy. We carry out a structural analysis that provides mechanistic...

journal_title：ACS medicinal chemistry letters

authors： Fernández A

更新日期：2020-08-17 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：: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：: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：:Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, 2) and cethromycin (CET, 6), both of which are sem...

journal_title：ACS medicinal chemistry letters

authors： Wagh B,Paul T,Debrosse C,Klepacki D,Small MC,Mackerell AD Jr,Andrade RB

更新日期：2013-11-14 00:00:00

abstract：:Reactive oxygen species, contributing to oxidant-antioxidant imbalance, initiate damage to the airways cells, inflammatory processes, and further pathophysiological effects. Enhancing antioxidant properties is the main prophylactic and therapeutic challenge. In this work, a newly synthesized and biocompatible structur...

journal_title：ACS medicinal chemistry letters

authors： Wiśniewski M,Bieniek A,Roszek K,Czarnecka J,Bolibok P,Ferrer P,da Silva I,Terzyk AP

更新日期：2018-11-19 00:00:00

abstract：:Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinas...

journal_title：ACS medicinal chemistry letters

authors： Alder CM,Ambler M,Campbell AJ,Champigny AC,Deakin AM,Harling JD,Harris CA,Longstaff T,Lynn S,Maxwell AC,Mooney CJ,Scullion C,Singh OM,Smith IE,Somers DO,Tame CJ,Wayne G,Wilson C,Woolven JM

更新日期：2013-08-12 00:00:00

abstract：:[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...

journal_title：ACS medicinal chemistry letters

authors： Kaiser TM,Dentmon ZW,Dalloul CE,Sharma SK,Liotta DC

更新日期：2020-06-24 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：: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：:Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no SAR studies have been conducted on the noviose appendage, which represents the rate-l...

journal_title：ACS medicinal chemistry letters

authors： Zhao H,Kusuma BR,Blagg BS

更新日期：2010-07-13 00:00:00

abstract：:In this work, we present an investigation into the physical properties of a unique class of aromatic boronic acids, the benzoxaboroles. Using spectrophotometric methods, the ionization constants of a family of substituted benzoxaboroles are determined. Heterocyclic ring modifications are examined to determine their ef...

journal_title：ACS medicinal chemistry letters

authors： Tomsho JW,Pal A,Hall DG,Benkovic SJ

更新日期：2011-10-19 00:00:00

abstract：:Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. T...

journal_title：ACS medicinal chemistry letters

authors： Kallander LS,Washburn D,Hilfiker MA,Eidam HS,Lawhorn BG,Prendergast J,Fox R,Dowdell S,Manns S,Hoang T,Zhao S,Ye G,Hammond M,Holt DA,Roethke T,Hong X,Reid RA,Gampe R,Zhang H,Diaz E,Rendina AR,Quinn AM,Willette

更新日期：2018-07-02 00:00:00

abstract：:We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bio...

journal_title：ACS medicinal chemistry letters

authors： Yang MG,Xiao Z,Cherney RJ,Tebben AJ,Batt DG,Brown GD,Chen J,Cvijic ME,Dabros M,Duncia JV,Galella M,Gardner DS,Khandelwal P,Ko SS,Malley MF,Mo R,Pang J,Rose AV,Santella JB 3rd,Shi H,Srivastava A,Traeger SC,Wang

更新日期：2019-01-16 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：: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：:GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategi...

journal_title：ACS medicinal chemistry letters

authors： Brooks CA,Barton LS,Behm DJ,Eidam HS,Fox RM,Hammond M,Hoang TH,Holt DA,Hilfiker MA,Lawhorn BG,Patterson JR,Stoy P,Roethke TJ,Ye G,Zhao S,Thorneloe KS,Goodman KB,Cheung M

更新日期：2019-07-15 00:00:00

abstract：:Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathw...

journal_title：ACS medicinal chemistry letters

authors： Flaherty DP,Miller JR,Garshott DM,Hedrick M,Gosalia P,Li Y,Milewski M,Sugarman E,Vasile S,Salaniwal S,Su Y,Smith LH,Chung TD,Pinkerton AB,Aubé J,Callaghan MU,Golden JE,Fribley AM,Kaufman RJ

更新日期：2014-10-29 00:00:00

abstract：:This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inh...

journal_title：ACS medicinal chemistry letters

authors： Wilson DL,Meininger I,Strater Z,Steiner S,Tomlin F,Wu J,Jamali H,Krappmann D,Götz MG

更新日期：2016-01-15 00:00:00