De novo prediction of p-glycoprotein-mediated efflux liability for druglike compounds.

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：:The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are p...

journal_title：ACS medicinal chemistry letters

authors： Liu G,Gaines JC,Robbins KJ,Lazo ND

更新日期：2012-08-28 00:00:00

abstract：:The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a p...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Walsh SP,Yan Y,de Jesus RK,Shahripour A,Teumelsan N,Zhu Y,Ha S,Owens KA,Thomas-Fowlkes BS,Felix JP,Liu J,Kohler M,Priest BT,Bailey T,Brochu R,Alonso-Galicia M,Kaczorowski GJ,Roy S,Yang L,Mills SG,Garcia M

更新日期：2012-03-28 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：: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：:GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclizati...

journal_title：ACS medicinal chemistry letters

authors： Negoro N,Sasaki S,Mikami S,Ito M,Suzuki M,Tsujihata Y,Ito R,Harada A,Takeuchi K,Suzuki N,Miyazaki J,Santou T,Odani T,Kanzaki N,Funami M,Tanaka T,Kogame A,Matsunaga S,Yasuma T,Momose Y

更新日期：2010-06-18 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：: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：:We report the synthesis of a novel heat shock protein 90 (hsp90) inhibitor conjugated to a star polymer. Using reversible addition-fragmentation chain-transfer (RAFT) polymerization, we prepared star polymers comprised of PEG attached to a predesigned functional core. The stars were cross-linked using disulfide linker...

journal_title：ACS medicinal chemistry letters

authors： Kim SJ,Ramsey DM,Boyer C,Davis TP,McAlpine SR

更新日期：2013-07-25 00:00:00

abstract：:Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow t...

journal_title：ACS medicinal chemistry letters

authors： Wang Y,Wach JY,Sheehan P,Zhong C,Zhan C,Harris R,Almo SC,Bishop J,Haggarty SJ,Ramek A,Berry KN,O'Herin C,Koehler AN,Hung AW,Young DW

更新日期：2016-07-14 00:00:00

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：:We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in v...

journal_title：ACS medicinal chemistry letters

authors： Xue CB,Wang A,Han Q,Zhang Y,Cao G,Feng H,Huang T,Zheng C,Xia M,Zhang K,Kong L,Glenn J,Anand R,Meloni D,Robinson DJ,Shao L,Storace L,Li M,Hughes RO,Devraj R,Morton PA,Rogier DJ,Covington M,Scherle P,Diamond

更新日期：2011-10-05 00:00:00

abstract：:Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of ...

journal_title：ACS medicinal chemistry letters

authors： Szokol B,Gyulavári P,Kurkó I,Baska F,Szántai-Kis C,Greff Z,Orfi Z,Peták I,Pénzes K,Torka R,Ullrich A,Orfi L,Vántus T,Kéri G

更新日期：2014-01-30 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：: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：: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：:A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filg...

journal_title：ACS medicinal chemistry letters

authors： Newton AS,Deiana L,Puleo DE,Cisneros JA,Cutrona KJ,Schlessinger J,Jorgensen WL

更新日期：2017-05-17 00:00:00

abstract：:A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles...

journal_title：ACS medicinal chemistry letters

authors： Jiang Z,Liu X,Yuan Z,He H,Wang J,Zhang X,Gong Z,Hou L,Shen L,Guo F,Zhang J,Wang J,Xu D,Liu Z,Li H,Chen X,Long C,Li J,Chen S

更新日期：2019-06-24 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：: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：: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：:ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Zhu Y,Teumelsan N,Walsh SP,Shahripour A,Priest BT,Swensen AM,Felix JP,Brochu RM,Bailey T,Thomas-Fowlkes B,Pai LY,Hampton C,Corona A,Hernandez M,Metzger J,Forrest M,Zhou X,Owens K,Tong V,Parmee E,Roy S,K

更新日期：2016-05-12 00:00:00

abstract：:A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibit...

journal_title：ACS medicinal chemistry letters

authors： Hirata K,Kotoku M,Seki N,Maeba T,Maeda K,Hirashima S,Sakai T,Obika S,Hori A,Hase Y,Yamaguchi T,Katsuda Y,Hata T,Miyagawa N,Arita K,Nomura Y,Asahina K,Aratsu Y,Kamada M,Adachi T,Noguchi M,Doi S,Crowe P,Bradle

更新日期：2015-11-04 00:00:00

abstract：:This study was aimed at investigating the antitumor activity of novel 2-oxindole derivatives against a well-characterized human nonsmall cell lung cancer (NSCLC) cell line. Test compounds produced an antiproliferative activity in the low micromolar/submicromolar range of concentrations and significantly induced typica...

journal_title：ACS medicinal chemistry letters

authors： Nesi G,Sestito S,Mey V,Ricciardi S,Falasca M,Danesi R,Lapucci A,Breschi MC,Fogli S,Rapposelli S

更新日期：2013-10-18 00:00:00

abstract：:Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we repor...

journal_title：ACS medicinal chemistry letters

authors： Tutone M,Pibiri I,Perriera R,Campofelice A,Culletta G,Melfi R,Pace A,Almerico AM,Lentini L

更新日期：2020-02-18 00:00:00

abstract：:All eight of the major active metabolites of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed...

journal_title：ACS medicinal chemistry letters

authors： Li A,Yuan CC,Chow D,Chen M,Emery MG,Hale C,Zhang X,Subramanian R,St Jean DJ Jr,Komorowski R,Véniant M,Wang M,Fotsch C

更新日期：2011-09-13 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：: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：: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：: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