EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity.

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：: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：:A new category of cationic meso-thiophenium porphyrins are introduced as possible alternatives to the popular meso-pyridinium porphyrins. Combinations of cationic porphyrins bearing meso-2-methylthiophenium and meso-4-hydroxyphenyl moieties T2(OH)2M (A2B2 type) and T(OH)3M (AB3 type) along with their zinc(II) complexe...

journal_title：ACS medicinal chemistry letters

authors： Mazumdar ZH,Sharma D,Mukherjee A,Basu S,Shukla PK,Jha T,Sengupta D

更新日期：2020-09-10 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：: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：:Carbazoles represent a family of tricyclic compounds that widely appeared in nature. Numerous studies have revealed a diverse array of bioactivity associated with this scaffold. In the present study, a novel and highly efficient methodology for preparing 1,3-dihydroxy-2-carboxycarbazole from indole-3-acetic acid and M...

journal_title：ACS medicinal chemistry letters

authors： Liu K,Zhang S

更新日期：2015-07-10 00:00:00

abstract：:Natural and synthetic histone deacetylase (HDAC) inhibitors generally derive their strong binding affinity and high potency from a key functional group that binds to the Zn(2+) ion within the enzyme active site. However, this feature is also thought to carry the potential liability of undesirable off-target interactio...

journal_title：ACS medicinal chemistry letters

authors： Vickers CJ,Olsen CA,Leman LJ,Ghadiri MR

更新日期：2012-04-26 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：:A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated i...

journal_title：ACS medicinal chemistry letters

authors： Rao AU,Shao N,Aslanian RG,Chan TY,Degrado SJ,Wang L,McKittrick B,Senior M,West RE Jr,Williams SM,Wu RL,Hwa J,Patel B,Zheng S,Sondey C,Palani A

更新日期：2011-11-21 00:00:00

abstract：:The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...

journal_title：ACS medicinal chemistry letters

authors： Cee VJ,Chavez F Jr,Herberich B,Lanman BA,Pettus LH,Reed AB,Wu B,Wurz RP,Andrews KL,Chen J,Hickman D,Laszlo J 3rd,Lee MR,Guerrero N,Mattson BK,Nguyen Y,Mohr C,Rex K,Sastri CE,Wang P,Wu Q,Wu T,Xu Y,Zhou Y,Wi

更新日期：2016-02-12 00:00:00

abstract：:WaterMap and MM-GB/SA scoring methods were applied to an extensive congeneric series of small-molecule SRC inhibitors with high-quality enzyme data and well characterized binding modes to compare the performance of these scoring methods in this data set and to provide insight into the relative strengths of each method...

journal_title：ACS medicinal chemistry letters

authors： Kohlmann A,Zhu X,Dalgarno D

更新日期：2012-01-06 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：: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：:In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular model...

journal_title：ACS medicinal chemistry letters

authors： Wu WL,Hao J,Domalski M,Burnett DA,Pissarnitski D,Zhao Z,Stamford A,Scapin G,Gao YD,Soriano A,Kelly TM,Yao Z,Powles MA,Chen S,Mei H,Hwa J

更新日期：2016-03-12 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：: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：: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：: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：: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：:Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (9a-f) or hippuric (11a,b) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker...

journal_title：ACS medicinal chemistry letters

authors： Eldehna WM,Nocentini A,Elsayed ZM,Al-Warhi T,Aljaeed N,Alotaibi OJ,Al-Sanea MM,Abdel-Aziz HA,Supuran CT

更新日期：2020-03-18 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

abstract：:Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include th...

journal_title：ACS medicinal chemistry letters

authors： Haikarainen T,Narwal M,Joensuu P,Lehtiö L

更新日期：2013-11-20 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：:Visible light-mediated photocatalysis, which relies on the ability of photocatalysts to absorb low-energy visible light and engage in single-electron transfer (SET) or energy transfer (ET) processes with organic substrates, has emerged as one of the fastest growing fields in organic synthesis. This catalytic platform ...

journal_title：ACS medicinal chemistry letters

authors： Li P,Terrett JA,Zbieg JR

更新日期：2020-09-21 00:00:00

abstract：:IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and p...

journal_title：ACS medicinal chemistry letters

authors： Kerns JK,Busch-Petersen J,Fu W,Boehm JC,Nie H,Muratore M,Bullion A,Lin G,Li H,Davis R,Lin X,Lakdawala AS,Cousins R,Field R,Payne J,Miller DD,Bamborough P,Christopher JA,Baldwin I,Osborn RR,Yonchuk J,Webb E,Rum

更新日期：2018-10-30 00:00:00

abstract：:Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic ...

journal_title：ACS medicinal chemistry letters

authors： Kuduk SD,Chang RK,Greshock TJ,Ray WJ,Ma L,Wittmann M,Seager MA,Koeplinger KA,Thompson CD,Hartman GD,Bilodeau MT

更新日期：2012-10-13 00:00:00

abstract：:A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold w...

journal_title：ACS medicinal chemistry letters

authors： Li Q,Groaz E,Persoons L,Daelemans D,Herdewijn P

更新日期：2020-07-09 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：: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：: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