abstract：:The construction of bioactive peptides using β-amino acid-containing sequence patterns is a very promising strategy to obtain analogues that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of ...

journal_title：Journal of medicinal chemistry

authors： Cabrele C,Martinek TA,Reiser O,Berlicki Ł

更新日期：2014-12-11 00:00:00

abstract：:To better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of ∼3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found ...

journal_title：Journal of medicinal chemistry

authors： Brown DG,May-Dracka TL,Gagnon MM,Tommasi R

更新日期：2014-12-11 00:00:00

abstract：:The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardi...

journal_title：Journal of medicinal chemistry

authors： Epstein O,Bryan MC,Cheng AC,Derakhchan K,Dineen TA,Hickman D,Hua Z,Human JB,Kreiman C,Marx IE,Weiss MM,Wahl RC,Wen PH,Whittington DA,Wood S,Zheng XM,Fremeau RT Jr,White RD,Patel VF

更新日期：2014-12-11 00:00:00

abstract：:8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell ...

journal_title：Journal of medicinal chemistry

authors： Jesus AR,Dias C,Matos AM,de Almeida RF,Viana AS,Marcelo F,Ribeiro RT,Macedo MP,Airoldi C,Nicotra F,Martins A,Cabrita EJ,Jiménez-Barbero J,Rauter AP

更新日期：2014-11-26 00:00:00

abstract：:Neutrophil serine proteases, proteinase 3 (PR3) and human neutrophil elastase (HNE), are considered as targets for chronic inflammatory diseases. Despite sharing high sequence similarity, the two enzymes have different substrate specificities and functions. While a plethora of HNE inhibitors exist, PR3 specific inhibi...

journal_title：Journal of medicinal chemistry

authors： Budnjo A,Narawane S,Grauffel C,Schillinger AS,Fossen T,Reuter N,Haug BE

更新日期：2014-11-26 00:00:00

abstract：:Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4-cyclin D1 in vitro. Compound 1 blocks the growth of cancer cells at G0/G1 phase of the cell cycle. It also blocks the cell cycle at G2/M phase, which is explained by the...

journal_title：Journal of medicinal chemistry

authors： Mahale S,Bharate SB,Manda S,Joshi P,Bharate SS,Jenkins PR,Vishwakarma RA,Chaudhuri B

更新日期：2014-11-26 00:00:00

abstract：:Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the c...

journal_title：Journal of medicinal chemistry

authors： Menet CJ,Fletcher SR,Van Lommen G,Geney R,Blanc J,Smits K,Jouannigot N,Deprez P,van der Aar EM,Clement-Lacroix P,Lepescheux L,Galien R,Vayssiere B,Nelles L,Christophe T,Brys R,Uhring M,Ciesielski F,Van Rompaey L

更新日期：2014-11-26 00:00:00

abstract：:Polycomb Repressive Complex 2 (PRC2) modulates the chromatin structure and transcriptional repression by trimethylation lysine 27 of histone H3 (H3K27me3), a process that necessitates the protein-protein interaction (PPI) between the catalytic subunit EZH2 and EED. Deregulated PRC2 is intimately involved in tumorigene...

journal_title：Journal of medicinal chemistry

authors： Kong X,Chen L,Jiao L,Jiang X,Lian F,Lu J,Zhu K,Du D,Liu J,Ding H,Zhang N,Shen J,Zheng M,Chen K,Liu X,Jiang H,Luo C

更新日期：2014-11-26 00:00:00

abstract：:CXCL12 binds to CXCR4, promoting both chemotaxis of lymphocytes and metastasis of cancer cells. We previously identified small molecule ligands that bind CXCL12 and block CXCR4-mediated chemotaxis. We now report a 1.9 Å resolution X-ray structure of CXCL12 bound by such a molecule at a site normally bound by sY21 of C...

journal_title：Journal of medicinal chemistry

authors： Smith EW,Liu Y,Getschman AE,Peterson FC,Ziarek JJ,Li R,Volkman BF,Chen Y

更新日期：2014-11-26 00:00:00

abstract：:Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid in...

journal_title：Journal of medicinal chemistry

authors： Nara H,Sato K,Naito T,Mototani H,Oki H,Yamamoto Y,Kuno H,Santou T,Kanzaki N,Terauchi J,Uchikawa O,Kori M

更新日期：2014-11-13 00:00:00

abstract：:Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compo...

journal_title：Journal of medicinal chemistry

authors： Grillot AL,Le Tiran A,Shannon D,Krueger E,Liao Y,O'Dowd H,Tang Q,Ronkin S,Wang T,Waal N,Li P,Lauffer D,Sizensky E,Tanoury J,Perola E,Grossman TH,Doyle T,Hanzelka B,Jones S,Dixit V,Ewing N,Liao S,Boucher B,Ja

更新日期：2014-11-13 00:00:00

abstract：:Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, includin...

journal_title：Journal of medicinal chemistry

authors： Kiss LE,Soares-da-Silva P

更新日期：2014-11-13 00:00:00

abstract：:The sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-ac...

journal_title：Journal of medicinal chemistry

authors： Jensen JE,Cristofori-Armstrong B,Anangi R,Rosengren KJ,Lau CH,Mobli M,Brust A,Alewood PF,King GF,Rash LD

更新日期：2014-11-13 00:00:00

abstract：:Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippoca...

journal_title：Journal of medicinal chemistry

authors： Scott JS,Bowker SS,Brocklehurst KJ,Brown HS,Clarke DS,Easter A,Ertan A,Goldberg K,Hudson JA,Kavanagh S,Laber D,Leach AG,MacFaul PA,Martin EA,McKerrecher D,Schofield P,Svensson PH,Teague J

更新日期：2014-11-13 00:00:00

abstract：:Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were...

journal_title：Journal of medicinal chemistry

authors： Liu Z,Yao Y,Kogiso M,Zheng B,Deng L,Qiu JJ,Dong S,Lv H,Gallo JM,Li XN,Song Y

更新日期：2014-10-23 00:00:00

abstract：:Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promi...

journal_title：Journal of medicinal chemistry

authors： Yu LF,Zhang HK,Caldarone BJ,Eaton JB,Lukas RJ,Kozikowski AP

更新日期：2014-10-23 00:00:00

abstract：:The G protein-coupled chemokine receptors CXCR1 and CXCR2 play key roles in inflammatory diseases and carcinogenesis. In inflammation, they activate and recruit polymorphonuclear cells (PMNs) through binding of the chemokines CXCL1 (CXCR1) and CXCL8 (CXCR1 and CXCR2). Structure-activity studies that examined the effec...

journal_title：Journal of medicinal chemistry

authors： Maeda DY,Peck AM,Schuler AD,Quinn MT,Kirpotina LN,Wicomb WN,Fan GH,Zebala JA

更新日期：2014-10-23 00:00:00

abstract：:Deregulation of CK1 (casein kinase 1) activity can be involved in the development of several pathological disorders and diseases such as cancer. Therefore, research interest in identifying potent CK1-specific inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1δ/ε-speci...

journal_title：Journal of medicinal chemistry

authors： Richter J,Bischof J,Zaja M,Kohlhof H,Othersen O,Vitt D,Alscher V,Pospiech I,García-Reyes B,Berg S,Leban J,Knippschild U

更新日期：2014-10-09 00:00:00

abstract：:Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflamm...

journal_title：Journal of medicinal chemistry

authors： Gosmini R,Nguyen VL,Toum J,Simon C,Brusq JM,Krysa G,Mirguet O,Riou-Eymard AM,Boursier EV,Trottet L,Bamborough P,Clark H,Chung CW,Cutler L,Demont EH,Kaur R,Lewis AJ,Schilling MB,Soden PE,Taylor S,Walker AL,Walker

更新日期：2014-10-09 00:00:00

abstract：:At present, the legendary magic bullet, i.e., a drug with high potency and selectivity toward a specific biological target, shares the spotlight with an emerging and alternative polypharmacology approach. Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. ...

journal_title：Journal of medicinal chemistry

authors： Anighoro A,Bajorath J,Rastelli G

更新日期：2014-10-09 00:00:00

abstract：:A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4...

journal_title：Journal of medicinal chemistry

authors： Ivachtchenko AV,Mitkin OD,Yamanushkin PM,Kuznetsova IV,Bulanova EA,Shevkun NA,Koryakova AG,Karapetian RN,Bichko VV,Trifelenkov AS,Kravchenko DV,Vostokova NV,Veselov MS,Chufarova NV,Ivanenkov YA

更新日期：2014-09-25 00:00:00

abstract：:Following erythrocyte invasion, malaria parasites export a catalogue of remodeling proteins into the infected cell that enable parasite development in the human host. Export is dependent on the activity of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins within the Plasmodium export element (PEXEL; Rx...

journal_title：Journal of medicinal chemistry

authors： Sleebs BE,Gazdik M,O'Neill MT,Rajasekaran P,Lopaticki S,Lackovic K,Lowes K,Smith BJ,Cowman AF,Boddey JA

更新日期：2014-09-25 00:00:00

abstract：:N6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family, has shown in humans many biological actions, including antitumoral effects through the modulation of the farnesyl pyrophosphate synthase (FPPS) activity. To investigate the relationship between i6A and FPPS, we undertook an inverse...

journal_title：Journal of medicinal chemistry

authors： Scrima M,Lauro G,Grimaldi M,Di Marino S,Tosco A,Picardi P,Gazzerro P,Riccio R,Novellino E,Bifulco M,Bifulco G,D'Ursi AM

更新日期：2014-09-25 00:00:00

abstract：:A facile route to perillyl alcohol (POH) differential glycosylation and the corresponding synthesis of a set of 34 POH glycosides is reported. Subsequent in vitro studies revealed a sugar dependent antiproliferative activity and the inhibition of S6 ribosomal protein phosphorylation as a putative mechanism of represen...

journal_title：Journal of medicinal chemistry

authors： Nandurkar NS,Zhang J,Ye Q,Ponomareva LV,She QB,Thorson JS

更新日期：2014-09-11 00:00:00

abstract：:Compounds acting via the neurotensin receptor type 2 (NTS2) are known to be active in animal models of acute and chronic pain. To identify novel NTS2 selective analgesics, we searched for NTS2 selective nonpeptide compounds using a FLIPR assay and identified the title compound (NTRC-824, 5) that, to our knowledge, is ...

journal_title：Journal of medicinal chemistry

authors： Thomas JB,Giddings AM,Wiethe RW,Olepu S,Warner KR,Sarret P,Gendron L,Longpre JM,Zhang Y,Runyon SP,Gilmour BP

更新日期：2014-09-11 00:00:00

abstract：:We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable o...

journal_title：Journal of medicinal chemistry

authors： Zhang W,DeRyckere D,Hunter D,Liu J,Stashko MA,Minson KA,Cummings CT,Lee M,Glaros TG,Newton DL,Sather S,Zhang D,Kireev D,Janzen WP,Earp HS,Graham DK,Frye SV,Wang X

更新日期：2014-08-28 00:00:00

abstract：:Seven transmembrane receptors (7TMRs), also known as G-protein-coupled receptors (GPCRs), have proven to be valuable targets for the development of therapeutics. The expansion of our understanding of 7TMR downstream signaling pathways beyond G-proteins has broadened our appreciation of the versatility of these cell su...

journal_title：Journal of medicinal chemistry

authors： Correll CC,McKittrick BA

更新日期：2014-08-28 00:00:00

abstract：:A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were ...

journal_title：Journal of medicinal chemistry

authors： Hamulakova S,Janovec L,Hrabinova M,Spilovska K,Korabecny J,Kristian P,Kuca K,Imrich J

更新日期：2014-08-28 00:00:00

abstract：:A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expr...

journal_title：Journal of medicinal chemistry

authors： Tafesse L,Kanemasa T,Kurose N,Yu J,Asaki T,Wu G,Iwamoto Y,Yamaguchi Y,Ni C,Engel J,Tsuno N,Patel A,Zhou X,Shintani T,Brown K,Hasegawa T,Shet M,Iso Y,Kato A,Kyle DJ

更新日期：2014-08-14 00:00:00

abstract：:Di-tert-butyl (E)-4,4'-stilbenedicarboxylate and tert-butyl 4-vinylbenzoate were copolymerized with maleic anhydride and tert-butyl 4-maleimidobenzoate, individually and respectively. After conversion into polyanions, these four copolymers exhibited activity against four HIV-1 strains: IIIb, BaL, JR-CSF, and 92UG037. ...

journal_title：Journal of medicinal chemistry

authors： Savage AM,Li Y,Matolyak LE,Doncel GF,Turner SR,Gandour RD

更新日期：2014-08-14 00:00:00

abstract：:Cathepsin B (CTB) is a cysteine protease believed to be an important therapeutic target or biomarker for several diseases including aggressive cancer, arthritis, and parasitic infections. The development of probes capable of assessing CTB activity in cell lysates, living cells, and animal models of disease are needed ...

journal_title：Journal of medicinal chemistry

authors： Chowdhury MA,Moya IA,Bhilocha S,McMillan CC,Vigliarolo BG,Zehbe I,Phenix CP

更新日期：2014-07-24 00:00:00

abstract：:Translocator protein (18 kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such stud...

journal_title：Journal of medicinal chemistry

authors： Brouwer C,Jenko K,Zoghbi SS,Innis RB,Pike VW

更新日期：2014-07-24 00:00:00

abstract：:Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the clinic for PDE4 inhibitors, primarily due to PDE4 mediated side effe...

journal_title：Journal of medicinal chemistry

authors： Felding J,Sørensen MD,Poulsen TD,Larsen J,Andersson C,Refer P,Engell K,Ladefoged LG,Thormann T,Vinggaard AM,Hegardt P,Søhoel A,Nielsen SF

更新日期：2014-07-24 00:00:00

abstract：:A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, a...

journal_title：Journal of medicinal chemistry

authors： Shang R,Pu X,Xu X,Xin Z,Zhang C,Guo W,Liu Y,Liang J

更新日期：2014-07-10 00:00:00

abstract：:Protecting enkephalins, endogenous opioid peptides released in response to nociceptive stimuli, is an innovative approach for acute and neuropathic pain alleviation. This is achieved by inhibition of their enzymatic degradation by two membrane-bound Zn-metallopeptidases, neprilysin (NEP, EC 3.4.24.11) and aminopeptida...

journal_title：Journal of medicinal chemistry

authors： Poras H,Bonnard E,Dangé E,Fournié-Zaluski MC,Roques BP

更新日期：2014-07-10 00:00:00

abstract：:Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as...

journal_title：Journal of medicinal chemistry

authors： Burch JD,Lau K,Barker JJ,Brookfield F,Chen Y,Chen Y,Eigenbrot C,Ellebrandt C,Ismaili MH,Johnson A,Kordt D,MacKinnon CH,McEwan PA,Ortwine DF,Stein DB,Wang X,Winkler D,Yuen PW,Zhang Y,Zarrin AA,Pei Z

更新日期：2014-07-10 00:00:00

abstract：:Novel bisbenzimidazole inhibitors of bacterial type IA topoisomerase are of interest for the development of new antibacterial agents that are impacted by target-mediated cross resistance with fluoroquinolones. The present study demonstrates the successful synthesis and evaluation of bisbenzimidazole analogues as Esche...

journal_title：Journal of medicinal chemistry

authors： Nimesh H,Sur S,Sinha D,Yadav P,Anand P,Bajaj P,Virdi JS,Tandon V

更新日期：2014-06-26 00:00:00

abstract：:Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative...

journal_title：Journal of medicinal chemistry

authors： Loksha YM,Pedersen EB,Loddo R,Sanna G,Collu G,Giliberti G,La Colla P

更新日期：2014-06-26 00:00:00

abstract：:Modulation of sphingosine 1-phosphate (S1P) signaling represents a solid opportunity for multiple sclerosis (MS) treatment. In this issue, a team at Novartis reports on the identification of the first direct S1P lyase (S1PL) inhibitors as new MS agents. One of the most potent inhibitors reported in their work was demo...

journal_title：Journal of medicinal chemistry

authors： Cosconati S,Novellino E

更新日期：2014-06-26 00:00:00

abstract：:G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A se...

journal_title：Journal of medicinal chemistry

authors： Setoh M,Ishii N,Kono M,Miyanohana Y,Shiraishi E,Harasawa T,Ota H,Odani T,Kanzaki N,Aoyama K,Hamada T,Kori M

更新日期：2014-06-26 00:00:00