abstract：:K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras-PDEδ intera...

journal_title：Journal of medicinal chemistry

authors： Zimmermann G,Schultz-Fademrecht C,Küchler P,Murarka S,Ismail S,Triola G,Nussbaumer P,Wittinghofer A,Waldmann H

更新日期：2014-06-26 00:00:00

abstract：:A comparison of the effects of the 6-(2-chloro-6-fluorobenzyl)-2-(alkylthio)pyrimidin-4(3H)-ones (2-Cl-6-F-S-DABOs) 7-12 and the related 6-(2,6-difluorobenzyl) counterparts 13-15 in HIV-1 infected cells and in the HIV-1 reverse transcriptase (RT) assays is here described. The new 2-Cl-6-F-S-DABOs showed up to picomola...

journal_title：Journal of medicinal chemistry

authors： Rotili D,Tarantino D,Nawrozkij MB,Babushkin AS,Botta G,Marrocco B,Cirilli R,Menta S,Badia R,Crespan E,Ballante F,Ragno R,Esté JA,Maga G,Mai A

更新日期：2014-06-26 00:00:00

abstract：:Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of he...

journal_title：Journal of medicinal chemistry

authors： Weiss JT,Dawson JC,Fraser C,Rybski W,Torres-Sánchez C,Bradley M,Patton EE,Carragher NO,Unciti-Broceta A

更新日期：2014-06-26 00:00:00

abstract：:Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1-3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several ty...

journal_title：Journal of medicinal chemistry

authors： Marzaro G,Coluccia A,Ferrarese A,Brun P,Castagliuolo I,Conconi MT,La Regina G,Bai R,Silvestri R,Hamel E,Chilin A

更新日期：2014-06-12 00:00:00

abstract：:We recently introduced sulfated pentagalloylglucopyranoside (SPGG) as an allosteric inhibitor of factor XIa (FXIa) (Al-Horani et al., J. Med Chem. 2013, 56, 867-878). To better understand the SPGG-FXIa interaction, we utilized eight SPGG variants and a range of biochemical techniques. The results reveal that SPGG's su...

journal_title：Journal of medicinal chemistry

authors： Al-Horani RA,Desai UR

更新日期：2014-06-12 00:00:00

abstract：:Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was emp...

journal_title：Journal of medicinal chemistry

authors： Kawatkar SP,Keating TA,Olivier NB,Breen JN,Green OM,Guler SY,Hentemann MF,Loch JT,McKenzie AR,Newman JV,Otterson LG,Martínez-Botella G

更新日期：2014-06-12 00:00:00

abstract：:We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong ...

journal_title：Journal of medicinal chemistry

authors： Suchaud V,Bailly F,Lion C,Calmels C,Andréola ML,Christ F,Debyser Z,Cotelle P

更新日期：2014-06-12 00:00:00

abstract：:A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT...

journal_title：Journal of medicinal chemistry

authors： Lee HY,Tsai AC,Chen MC,Shen PJ,Cheng YC,Kuo CC,Pan SL,Liu YM,Liu JF,Yeh TK,Wang JC,Chang CY,Chang JY,Liou JP

更新日期：2014-05-22 00:00:00

abstract：:C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipi...

journal_title：Journal of medicinal chemistry

authors： Tenti G,Parada E,León R,Egea J,Martínez-Revelles S,Briones AM,Sridharan V,López MG,Ramos MT,Menéndez JC

更新日期：2014-05-22 00:00:00

abstract：:Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate...

journal_title：Journal of medicinal chemistry

authors： Németh G,Greff Z,Sipos A,Varga Z,Székely R,Sebestyén M,Jászay Z,Béni S,Nemes Z,Pirat JL,Volle JN,Virieux D,Gyuris Á,Kelemenics K,Ay E,Minarovits J,Szathmary S,Kéri G,Orfi L

更新日期：2014-05-22 00:00:00

abstract：:To determine if the conjugation of a small receptor ligand to a peptidic carrier to potentially facilitate transport across the blood-brain barrier (BBB) by "molecular Trojan horse" transcytosis is feasible, we synthesized several transport peptide-fallypride fusion molecules as model systems and determined their bind...

journal_title：Journal of medicinal chemistry

authors： Wängler C,Chowdhury S,Höfner G,Djurova P,Purisima EO,Bartenstein P,Wängler B,Fricker G,Wanner KT,Schirrmacher R

更新日期：2014-05-22 00:00:00

abstract：:(-)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinson's d...

journal_title：Journal of medicinal chemistry

authors： Naidoo J,De Jesus-Cortes H,Huntington P,Estill S,Morlock LK,Starwalt R,Mangano TJ,Williams NS,Pieper AA,Ready JM

更新日期：2014-05-08 00:00:00

abstract：:3',5'-Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger that regulates numerous biological processes under physiological and pathological conditions, including cancer, diabetes, heart failure, inflammation, and neurological disorders. In the past, all effects of cAMP were initially believed to be med...

journal_title：Journal of medicinal chemistry

authors： Chen H,Wild C,Zhou X,Ye N,Cheng X,Zhou J

更新日期：2014-05-08 00:00:00

abstract：:Drug-resistant bacterial infections and lack of available antibacterial agents in clinical practice are becoming serious risks to public health. We synthesized a new class of haloemodins by modifying a traditional Chinese medicine component, emodin. The novel haloemodin exerts strong inhibitory activity on bacterial t...

journal_title：Journal of medicinal chemistry

authors： Duan F,Li X,Cai S,Xin G,Wang Y,Du D,He S,Huang B,Guo X,Zhao H,Zhang R,Ma L,Liu Y,Du Q,Wei Z,Xing Z,Liang Y,Wu X,Fan C,Ji C,Zeng D,Chen Q,He Y,Liu X,Huang W

更新日期：2014-05-08 00:00:00

abstract：:A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited H...

journal_title：Journal of medicinal chemistry

authors： Costi R,Métifiot M,Chung S,Cuzzucoli Crucitti G,Maddali K,Pescatori L,Messore A,Madia VN,Pupo G,Scipione L,Tortorella S,Di Leva FS,Cosconati S,Marinelli L,Novellino E,Le Grice SF,Corona A,Pommier Y,Marchand C,Di San

更新日期：2014-04-24 00:00:00

abstract：:Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand ef...

journal_title：Journal of medicinal chemistry

authors： Crawford TD,Ndubaku CO,Chen H,Boggs JW,Bravo BJ,Delatorre K,Giannetti AM,Gould SE,Harris SF,Magnuson SR,McNamara E,Murray LJ,Nonomiya J,Sambrone A,Schmidt S,Smyczek T,Stanley M,Vitorino P,Wang L,West K,Wu P,Ye W

更新日期：2014-04-24 00:00:00

abstract：:A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less tha...

journal_title：Journal of medicinal chemistry

authors： Chapman TM,Osborne SA,Wallace C,Birchall K,Bouloc N,Jones HM,Ansell KH,Taylor DL,Clough B,Green JL,Holder AA

更新日期：2014-04-24 00:00:00

abstract：:In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected a...

journal_title：Journal of medicinal chemistry

authors： Biftu T,Sinha-Roy R,Chen P,Qian X,Feng D,Kuethe JT,Scapin G,Gao YD,Yan Y,Krueger D,Bak A,Eiermann G,He J,Cox J,Hicks J,Lyons K,He H,Salituro G,Tong S,Patel S,Doss G,Petrov A,Wu J,Xu SS,Sewall C,Zhang X,

更新日期：2014-04-24 00:00:00

abstract：:We have previously described a cyclic tetrapeptide, 1, that displays μ opioid receptor (MOPr) agonist and δ opioid receptor (DOPr) antagonist activity, a profile associated with a reduced incidence of opioid tolerance and dependence. Like many peptides, 1 has poor bioavailability. We describe here an analogue of 1 wit...

journal_title：Journal of medicinal chemistry

authors： Mosberg HI,Yeomans L,Anand JP,Porter V,Sobczyk-Kojiro K,Traynor JR,Jutkiewicz EM

更新日期：2014-04-10 00:00:00

abstract：:Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-,...

journal_title：Journal of medicinal chemistry

authors： Li Y,St Louis L,Knapp BI,Muthu D,Anglin B,Giuvelis D,Bidlack JM,Bilsky EJ,Polt R

更新日期：2014-03-27 00:00:00

abstract：:Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) has been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targe...

journal_title：Journal of medicinal chemistry

authors： Yan L,Yan C,Qian K,Su H,Kofsky-Wofford SA,Lee WC,Zhao X,Ho MC,Ivanov I,Zheng YG

更新日期：2014-03-27 00:00:00

abstract：:Insulin secretion by pancreatic β-cells in response to glucose or other secretagogues is tightly coupled to membrane potential. Various studies have highlighted the prospect of enhancing insulin secretion in a glucose-dependent manner by blocking voltage-gated potassium channels (K(v)) and calcium-activated potassium ...

journal_title：Journal of medicinal chemistry

authors： Nguyen TT,Folch B,Létourneau M,Truong NH,Doucet N,Fournier A,Chatenet D

更新日期：2014-03-27 00:00:00

abstract：:N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both P...

journal_title：Journal of medicinal chemistry

authors： Rackham MD,Brannigan JA,Rangachari K,Meister S,Wilkinson AJ,Holder AA,Leatherbarrow RJ,Tate EW

更新日期：2014-03-27 00:00:00

abstract：:Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addre...

journal_title：Journal of medicinal chemistry

authors： Moreau B,O'Meara JA,Bordeleau J,Garneau M,Godbout C,Gorys V,Leblanc M,Villemure E,White PW,Llinàs-Brunet M

更新日期：2014-03-13 00:00:00

abstract：:In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic...

journal_title：Journal of medicinal chemistry

authors： Talamas FX,Abbot SC,Anand S,Brameld KA,Carter DS,Chen J,Davis D,de Vicente J,Fung AD,Gong L,Harris SF,Inbar P,Labadie SS,Lee EK,Lemoine R,Le Pogam S,Leveque V,Li J,McIntosh J,Nájera I,Park J,Railkar A,Rajyagur

更新日期：2014-03-13 00:00:00

abstract：:A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the opt...

journal_title：Journal of medicinal chemistry

authors： Zhang N,Zhang X,Zhu J,Turpoff A,Chen G,Morrill C,Huang S,Lennox W,Kakarla R,Liu R,Li C,Ren H,Almstead N,Venkatraman S,Njoroge FG,Gu Z,Clausen V,Graci J,Jung SP,Zheng Y,Colacino JM,Lahser F,Sheedy J,Mollin A

更新日期：2014-03-13 00:00:00

abstract：:The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the pr...

journal_title：Journal of medicinal chemistry

authors： Scola PM,Wang AX,Good AC,Sun LQ,Combrink KD,Campbell JA,Chen J,Tu Y,Sin N,Venables BL,Sit SY,Chen Y,Cocuzza A,Bilder DM,D'Andrea S,Zheng B,Hewawasam P,Ding M,Thuring J,Li J,Hernandez D,Yu F,Falk P,Zhai G,S

更新日期：2014-03-13 00:00:00

abstract：:Conformationally restricted 2'-spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2'-oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS...

journal_title：Journal of medicinal chemistry

authors： Du J,Chun BK,Mosley RT,Bansal S,Bao H,Espiritu C,Lam AM,Murakami E,Niu C,Micolochick Steuer HM,Furman PA,Sofia MJ

更新日期：2014-03-13 00:00:00

abstract：:Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing (i) nanomolar potency in HCV replicon ce...

journal_title：Journal of medicinal chemistry

authors： Cummings MD,Lin TI,Hu L,Tahri A,McGowan D,Amssoms K,Last S,Devogelaere B,Rouan MC,Vijgen L,Berke JM,Dehertogh P,Fransen E,Cleiren E,van der Helm L,Fanning G,Nyanguile O,Simmen K,Van Remoortere P,Raboisson P,Vendev

更新日期：2014-03-13 00:00:00

abstract：:HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimizatio...

journal_title：Journal of medicinal chemistry

authors： Jiang Y,Andrews SW,Condroski KR,Buckman B,Serebryany V,Wenglowsky S,Kennedy AL,Madduru MR,Wang B,Lyon M,Doherty GA,Woodard BT,Lemieux C,Geck Do M,Zhang H,Ballard J,Vigers G,Brandhuber BJ,Stengel P,Josey JA,Beigelm

更新日期：2014-03-13 00:00:00

abstract：:The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) ...

journal_title：Journal of medicinal chemistry

authors： O'Hara F,Burns AC,Collins MR,Dalvie D,Ornelas MA,Vaz AD,Fujiwara Y,Baran PS

更新日期：2014-02-27 00:00:00

abstract：:Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transa...

journal_title：Journal of medicinal chemistry

authors： Harcken C,Riether D,Kuzmich D,Liu P,Betageri R,Ralph M,Emmanuel M,Reeves JT,Berry A,Souza D,Nelson RM,Kukulka A,Fadra TN,Zuvela-Jelaska L,Dinallo R,Bentzien J,Nabozny GH,Thomson DS

更新日期：2014-02-27 00:00:00

abstract：:Truncated N(6)-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N(6) and/or C2 substituents were tolerated in A3AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high...

journal_title：Journal of medicinal chemistry

authors： Nayak A,Chandra G,Hwang I,Kim K,Hou X,Kim HO,Sahu PK,Roy KK,Yoo J,Lee Y,Cui M,Choi S,Moss SM,Phan K,Gao ZG,Ha H,Jacobson KA,Jeong LS

更新日期：2014-02-27 00:00:00

abstract：:The study by Huang et al. is an excellent example of rational structure-based and lipophilic-efficiency optimization of crizotinib (Xalkori) aimed at novel ALK inhibitors capable of overcoming clinically acquired resistance against the current drug in NSCLC patients. One of the most promising new compounds, 8e, displa...

journal_title：Journal of medicinal chemistry

authors： Lu X,Ding K

更新日期：2014-02-27 00:00:00

abstract：:Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be imp...

journal_title：Journal of medicinal chemistry

authors： Staben ST,Feng JA,Lyle K,Belvin M,Boggs J,Burch JD,Chua CC,Cui H,DiPasquale AG,Friedman LS,Heise C,Koeppen H,Kotey A,Mintzer R,Oh A,Roberts DA,Rouge L,Rudolph J,Tam C,Wang W,Xiao Y,Young A,Zhang Y,Hoeflich K

更新日期：2014-02-13 00:00:00

abstract：:A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was stud...

journal_title：Journal of medicinal chemistry

authors： Nauš P,Caletková O,Konečný P,Džubák P,Bogdanová K,Kolář M,Vrbková J,Slavětínská L,Tloušt'ová E,Perlíková P,Hajdúch M,Hocek M

更新日期：2014-02-13 00:00:00

abstract：:Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluor...

journal_title：Journal of medicinal chemistry

authors： Galante E,Okamura T,Sander K,Kikuchi T,Okada M,Zhang MR,Robson M,Badar A,Lythgoe M,Koepp M,Årstad E

更新日期：2014-02-13 00:00:00

abstract：:With the emergence of oseltamivir-resistant influenza viruses and in view of a highly pathogenic flu pandemic, it is important to develop new anti-influenza agents. Here, the development of neuraminidase (NA) inhibitors that were designed to overcome resistance mechanisms along with unfavorable pharmacokinetic (PK) pr...

journal_title：Journal of medicinal chemistry

authors： Schade D,Kotthaus J,Riebling L,Kotthaus J,Müller-Fielitz H,Raasch W,Koch O,Seidel N,Schmidtke M,Clement B

更新日期：2014-02-13 00:00:00

abstract：:11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine comp...

journal_title：Journal of medicinal chemistry

authors： Goldberg FW,Dossetter AG,Scott JS,Robb GR,Boyd S,Groombridge SD,Kemmitt PD,Sjögren T,Gutierrez PM,deSchoolmeester J,Swales JG,Turnbull AV,Wild MJ

更新日期：2014-02-13 00:00:00

abstract：:Botulinum neurotoxins (BoNT) are the most potent toxins known and a significant bioterrorist threat. Few small molecule compounds have been identified that are active in cell-based or animal models, potentially due to toxin enzyme plasticity. Here we screened commercially available quinolinols, as well as synthesized ...

journal_title：Journal of medicinal chemistry

authors： Caglič D,Krutein MC,Bompiani KM,Barlow DJ,Benoni G,Pelletier JC,Reitz AB,Lairson LL,Houseknecht KL,Smith GR,Dickerson TJ

更新日期：2014-02-13 00:00:00