A Medicinal Chemist's Perspective on Transitioning from Industry to Academic Drug Discovery.

abstract：:The National Institutes of Health (NIH) closure of the agency's Center for Regenerative Medicine (CRM), which focused on therapeutic development of induced pluripotent stem cells (iPS), was caused by the lack of progress in practical development of the iPSs for use in human therapies. As the NIH evaluates priorities i...

journal_title：ACS medicinal chemistry letters

authors： Maguire G

更新日期：2014-10-08 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：: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：:A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust ph...

journal_title：ACS medicinal chemistry letters

authors： Walsh SP,Shahripour A,Tang H,Teumelsan N,Frie J,Zhu Y,Priest BT,Swensen AM,Liu J,Margulis M,Visconti R,Weinglass A,Felix JP,Brochu RM,Bailey T,Thomas-Fowlkes B,Alonso-Galicia M,Zhou X,Pai LY,Corona A,Hampton C,H

更新日期：2015-05-07 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：:Glucocorticoids are one of the most utilized and effective therapies in treating T-cell acute lymphoblastic leukemia. However, patients often develop resistance to glucocorticoids, rendering these therapies ineffective. We screened 9517 compounds, selected for their lead-like properties, chosen from among 3 372 615 co...

journal_title：ACS medicinal chemistry letters

authors： Cantley AM,Welsch M,Ambesi-Impiombato A,Sanchez-Martin M,Kim MY,Bauer A,Ferrando A,Stockwell BR

更新日期：2014-04-25 00:00:00

abstract：:The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (tw...

journal_title：ACS medicinal chemistry letters

authors： Praveen P,Tailhades J,Rosengren KJ,Liu M,Wade JD,Bathgate RAD,Hossain MA

更新日期：2020-10-22 00:00:00

abstract：:Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesira...

journal_title：ACS medicinal chemistry letters

authors： Johnson DS,Stiff C,Lazerwith SE,Kesten SR,Fay LK,Morris M,Beidler D,Liimatta MB,Smith SE,Dudley DT,Sadagopan N,Bhattachar SN,Kesten SJ,Nomanbhoy TK,Cravatt BF,Ahn K

更新日期：2011-02-10 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：:We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represe...

journal_title：ACS medicinal chemistry letters

authors： Elsadek B,Graeser R,Warnecke A,Unger C,Saleem T,El-Melegy N,Madkor H,Kratz F

更新日期：2010-05-26 00:00:00

abstract：:Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. ...

journal_title：ACS medicinal chemistry letters

authors： Oehlrich D,Peschiulli A,Tresadern G,Van Gool M,Vega JA,De Lucas AI,Alonso de Diego SA,Prokopcova H,Austin N,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Rombouts FJR,Macdonald G,Moechars D,Gijsen HJM,Trabanco AA

更新日期：2019-07-02 00:00:00

abstract：:Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (...

journal_title：ACS medicinal chemistry letters

authors： Vignaroli G,Zamperini C,Dreassi E,Radi M,Angelucci A,Sanità P,Crespan E,Kissova M,Maga G,Schenone S,Musumeci F,Botta M

更新日期：2013-05-20 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：: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 new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitr...

journal_title：ACS medicinal chemistry letters

authors： Tukulula M,Njoroge M,Abay ET,Mugumbate GC,Wiesner L,Taylor D,Gibhard L,Norman J,Swart KJ,Gut J,Rosenthal PJ,Barteau S,Streckfuss J,Kameni-Tcheudji J,Chibale K

更新日期：2013-10-01 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：: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：:Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the la...

journal_title：ACS medicinal chemistry letters

authors： Campbell JE,Kuntz KW,Knutson SK,Warholic NM,Keilhack H,Wigle TJ,Raimondi A,Klaus CR,Rioux N,Yokoi A,Kawano S,Minoshima Y,Choi HW,Porter Scott M,Waters NJ,Smith JJ,Chesworth R,Moyer MP,Copeland RA

更新日期：2015-03-04 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：:Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titrati...

journal_title：ACS medicinal chemistry letters

authors： Li S,Chen H,Yang X,Bardelang D,Wyman IW,Wan J,Lee SM,Wang R

更新日期：2015-10-16 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：:An efficient method for the reconstruction of the 9-dihydroerythromycin A macrolactone skeleton has been established. The key steps are oxidative cleavage at the 11,12-position and reconstruction after insertion of an appropriate functionalized amino alcohol. Novel 15-membered macrolides, we named as "11a-azalides", w...

journal_title：ACS medicinal chemistry letters

authors： Sugimoto T,Tanikawa T

更新日期：2010-12-30 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：: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：: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：:Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alt...

journal_title：ACS medicinal chemistry letters

authors： Popovici-Muller J,Lemieux RM,Artin E,Saunders JO,Salituro FG,Travins J,Cianchetta G,Cai Z,Zhou D,Cui D,Chen P,Straley K,Tobin E,Wang F,David MD,Penard-Lacronique V,Quivoron C,Saada V,de Botton S,Gross S,Dang L,Y

更新日期：2018-01-19 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：:Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alky...

journal_title：ACS medicinal chemistry letters

authors： Drakopoulos A,Tzitzoglaki C,McGuire K,Hoffmann A,Konstantinidi A,Kolokouris D,Ma C,Freudenberger K,Hutterer J,Gauglitz G,Wang J,Schmidtke M,Busath DD,Kolocouris A

更新日期：2018-01-29 00:00:00

abstract：:Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification o...

journal_title：ACS medicinal chemistry letters

authors： Hu Z,Banothu J,Beesu M,Gustafson CJ,Brush MJH,Trautman KL,Salyer ACD,Pathakumari B,David SA

更新日期：2018-12-20 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