Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672.

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：:The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for developme...

journal_title：ACS medicinal chemistry letters

authors： Sromek AW,Si YG,Zhang T,George SR,Seeman P,Neumeyer JL

更新日期：2011-03-10 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：:General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modificatio...

journal_title：ACS medicinal chemistry letters

authors： Fujimoto J,Kurasawa O,Takagi T,Liu X,Banno H,Kojima T,Asano Y,Nakamura A,Nambu T,Hata A,Ishii T,Sameshima T,Debori Y,Miyamoto M,Klein MG,Tjhen R,Sang BC,Levin I,Lane SW,Snell GP,Li K,Kefala G,Hoffman ID,Ding

更新日期：2019-09-19 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：:We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in v...

journal_title：ACS medicinal chemistry letters

authors： Chobanian HR,Guo Y,Liu P,Chioda MD,Fung S,Lanza TJ,Chang L,Bakshi RK,Dellureficio JP,Hong Q,McLaughlin M,Belyk KM,Krska SW,Makarewicz AK,Martel EJ,Leone JF,Frey L,Karanam B,Madeira M,Alvaro R,Shuman J,Salituro G

更新日期：2014-04-10 00:00:00

abstract：:ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse antic...

journal_title：ACS medicinal chemistry letters

authors： Peña-Solórzano D,Scholler M,Bernhardt G,Buschauer A,König B,Ochoa-Puentes C

更新日期：2018-07-25 00:00:00

abstract：:The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomai...

journal_title：ACS medicinal chemistry letters

authors： Demont EH,Bamborough P,Chung CW,Craggs PD,Fallon D,Gordon LJ,Grandi P,Hobbs CI,Hussain J,Jones EJ,Le Gall A,Michon AM,Mitchell DJ,Prinjha RK,Roberts AD,Sheppard RJ,Watson RJ

更新日期：2014-09-10 00:00:00

abstract：:A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...

journal_title：ACS medicinal chemistry letters

authors： Chatterjee J,Laufer B,Beck JG,Helyes Z,Pintér E,Szolcsányi J,Horvath A,Mandl J,Reubi JC,Kéri G,Kessler H

更新日期：2011-04-04 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：: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：: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：:Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design ...

journal_title：ACS medicinal chemistry letters

authors： Wang L,Doherty GA,Judd AS,Tao ZF,Hansen TM,Frey RR,Song X,Bruncko M,Kunzer AR,Wang X,Wendt MD,Flygare JA,Catron ND,Judge RA,Park CH,Shekhar S,Phillips DC,Nimmer P,Smith ML,Tahir SK,Xiao Y,Xue J,Zhang H,Le PN

更新日期：2020-03-30 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：:Representative d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety...

journal_title：ACS medicinal chemistry letters

authors： Zimmermann SC,Rais R,Alt J,Burzynski C,Slusher BS,Tsukamoto T

更新日期：2014-10-21 00:00:00

abstract：:Structure-activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-ba...

journal_title：ACS medicinal chemistry letters

authors： Leese MP,Jourdan F,Dohle W,Kimberley MR,Thomas MP,Bai R,Hamel E,Ferrandis E,Potter BV

更新日期：2012-01-12 00:00:00

abstract：:Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-a...

journal_title：ACS medicinal chemistry letters

authors： Hiesinger K,Schott A,Kramer JS,Blöcher R,Witt F,Wittmann SK,Steinhilber D,Pogoryelov D,Gerstmeier J,Werz O,Proschak E

更新日期：2019-10-30 00:00:00

abstract：:Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide-amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, whi...

journal_title：ACS medicinal chemistry letters

authors： Takayama K,Mori K,Sohma Y,Taketa K,Taguchi A,Yakushiji F,Minamino N,Miyazato M,Kangawa K,Hayashi Y

更新日期：2015-01-28 00:00:00

abstract：:Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested in vitro 18 NC inhibitors (NCIs) bearing a double functio...

journal_title：ACS medicinal chemistry letters

authors： Mori M,Dasso Lang MC,Saladini F,Palombi N,Kovalenko L,De Forni D,Poddesu B,Friggeri L,Giannini A,Malancona S,Summa V,Zazzi M,Mely Y,Botta M

更新日期：2018-12-07 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：: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：: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：: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：:The attachment of lipids to C- or N-terminally positioned lysine side-chain amino groups increases the activity of a short synthetic (Arg-Trp)3 antimicrobial peptide significantly, making these peptides even active against pathogenic Gram-negative bacteria. Thus, a peptide with strong activity against S. aureus (1.1-2...

journal_title：ACS medicinal chemistry letters

authors： Albada HB,Prochnow P,Bobersky S,Langklotz S,Schriek P,Bandow JE,Metzler-Nolte N

更新日期：2012-09-04 00:00:00

abstract：:Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food ...

journal_title：ACS medicinal chemistry letters

authors： Gambino A,Burnett JC,Koide K

更新日期：2020-01-09 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：:We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystalli...

journal_title：ACS medicinal chemistry letters

authors： Farand J,Kropf JE,Blomgren P,Xu J,Schmitt AC,Newby ZE,Wang T,Murakami E,Barauskas O,Sudhamsu J,Feng JY,Niedziela-Majka A,Schultz BE,Schwartz K,Viatchenko-Karpinski S,Kornyeyev D,Kashishian A,Fan P,Chen X,Lansdon EB

更新日期：2019-11-19 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 series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against b...

journal_title：ACS medicinal chemistry letters

authors： Wang S,Wang Y,Liu W,Liu N,Zhang Y,Dong G,Liu Y,Li Z,He X,Miao Z,Yao J,Li J,Zhang W,Sheng C

更新日期：2014-02-13 00:00:00

abstract：:Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was di...

journal_title：ACS medicinal chemistry letters

authors： Berton P,Di Bona KR,Yancey D,Rizvi SAA,Gray M,Gurau G,Shamshina JL,Rasco JF,Rogers RD

更新日期：2017-04-12 00:00:00