abstract：:Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2'-α-F-2'-β-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T muta...

journal_title：Journal of medicinal chemistry

authors： Zhen L,Dai L,Wen X,Yao L,Jin X,Yang XW,Zhao W,Yu SQ,Yuan H,Wang G,Sun H

更新日期：2017-07-27 00:00:00

abstract：:Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a-8a and 9a-e) with highe...

journal_title：Journal of medicinal chemistry

authors： Vignaroli G,Iovenitti G,Zamperini C,Coniglio F,Calandro P,Molinari A,Fallacara AL,Sartucci A,Calgani A,Colecchia D,Mancini A,Festuccia C,Dreassi E,Valoti M,Musumeci F,Chiariello M,Angelucci A,Botta M,Schenone S

更新日期：2017-07-27 00:00:00

abstract：:Understanding the "limits and boundaries" of the central nervous system (CNS) property space is a critical aspect of modern CNS drug design. Medicinal chemists are often guided by the physicochemical properties of marketed CNS drugs, which are heavily biased toward "traditional" aminergic targets and commonly describe...

journal_title：Journal of medicinal chemistry

authors： Rankovic Z

更新日期：2017-07-27 00:00:00

abstract：:To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and a...

journal_title：Journal of medicinal chemistry

authors： Min J,Guillen VS,Sharma A,Zhao Y,Ziegler Y,Gong P,Mayne CG,Srinivasan S,Kim SH,Carlson KE,Nettles KW,Katzenellenbogen BS,Katzenellenbogen JA

更新日期：2017-07-27 00:00:00

abstract：:The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the va...

journal_title：Journal of medicinal chemistry

authors： Dyckman AJ

更新日期：2017-07-13 00:00:00

abstract：:In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and an MTT assay for cytotoxicity. On the basis of their noteworthy a...

journal_title：Journal of medicinal chemistry

authors： Krieger V,Hamacher A,Gertzen CGW,Senger J,Zwinderman MRH,Marek M,Romier C,Dekker FJ,Kurz T,Jung M,Gohlke H,Kassack MU,Hansen FK

更新日期：2017-07-13 00:00:00

abstract：:In lead optimization, open, solvent-exposed protein pockets are often disregarded as prospective binding sites. Because of bulk-solvent proximity, researchers are instead enticed to attach charged polar groups at inhibitor scaffolds to improve solubility and pharmacokinetic properties. It is rarely considered that sol...

journal_title：Journal of medicinal chemistry

authors： Cramer J,Krimmer SG,Heine A,Klebe G

更新日期：2017-07-13 00:00:00

abstract：:The specificity of nucleic acids' binders is crucial for developing this kind of drug, especially for novel G-quadruplexes' binders. Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities. In order to improve the selectivity and binding affinity of quindoline derivative...

journal_title：Journal of medicinal chemistry

authors： Zeng DY,Kuang GT,Wang SK,Peng W,Lin SL,Zhang Q,Su XX,Hu MH,Wang H,Tan JH,Huang ZS,Gu LQ,Ou TM

更新日期：2017-07-13 00:00:00

abstract：:Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two diffe...

journal_title：Journal of medicinal chemistry

authors： Iwatani-Yoshihara M,Ito M,Klein MG,Yamamoto T,Yonemori K,Tanaka T,Miwa M,Morishita D,Endo S,Tjhen R,Qin L,Nakanishi A,Maezaki H,Kawamoto T

更新日期：2017-07-13 00:00:00

abstract：:Starting with a previously reported linear breast cancer targeting decapeptide WxEAAYQkFL, here we report the synthesis of a novel cyclic peptide analogue cyclic WXEAAYQkFL. The N- to C-terminus amide cyclized peptide with one d-amino acid (k) displayed higher uptake by breast cancer cells, with minimal uptake by the ...

journal_title：Journal of medicinal chemistry

authors： Raghuwanshi Y,Etayash H,Soudy R,Paiva I,Lavasanifar A,Kaur K

更新日期：2017-06-22 00:00:00

abstract：:Therapies based on activation of multiple Toll-like receptors (TLRs) may offer superior therapeutic profiles than that of single TLR activation. To discover new small molecules that could activate multiple TLRs, we performed a cell-based high-throughput screening of a small-molecule library based on TLR3-mediated NF-κ...

journal_title：Journal of medicinal chemistry

authors： Zhang L,Dewan V,Yin H

更新日期：2017-06-22 00:00:00

abstract：:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in...

journal_title：Journal of medicinal chemistry

authors： Cheng X,Merz KH,Vatter S,Zeller J,Muehlbeyer S,Thommet A,Christ J,Wölfl S,Eisenbrand G

更新日期：2017-06-22 00:00:00

abstract：:Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1...

journal_title：Journal of medicinal chemistry

authors： Fortin S,Charest-Morin X,Turcotte V,Lauvaux C,Lacroix J,Côté MF,Gobeil S,C-Gaudreault R

更新日期：2017-06-22 00:00:00

abstract：:Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARγ is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARγ with robust antidiabetic properties, which are confounded with signi...

journal_title：Journal of medicinal chemistry

authors： Frkic RL,He Y,Rodriguez BB,Chang MR,Kuruvilla D,Ciesla A,Abell AD,Kamenecka TM,Griffin PR,Bruning JB

更新日期：2017-06-08 00:00:00

abstract：:A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, ...

journal_title：Journal of medicinal chemistry

authors： Schnekenburger M,Goffin E,Lee JY,Jang JY,Mazumder A,Ji S,Rogister B,Bouider N,Lefranc F,Miklos W,Mathieu V,de Tullio P,Kim KW,Dicato M,Berger W,Han BW,Kiss R,Pirotte B,Diederich M

更新日期：2017-06-08 00:00:00

abstract：:Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated nonselective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approa...

journal_title：Journal of medicinal chemistry

authors： Qu C,Ding M,Zhu Y,Lu Y,Du J,Miller M,Tian J,Zhu J,Xu J,Wen M,Er-Bu A,Wang J,Xiao Y,Wu M,McManus OB,Li M,Wu J,Luo HR,Cao Z,Shen B,Wang H,Zhu MX,Hong X

更新日期：2017-06-08 00:00:00

abstract：:Polymeric nanoparticles (PNPs) may efficiently deliver in vivo therapeutics to tumors when conjugated to specific targeting agents. Gint4.T aptamer specifically recognizes platelet-derived growth factor receptor β and can cross the blood-brain barrier (BBB). We synthesized Gint4.T-conjugated PNPs able of high uptake i...

journal_title：Journal of medicinal chemistry

authors： Monaco I,Camorani S,Colecchia D,Locatelli E,Calandro P,Oudin A,Niclou S,Arra C,Chiariello M,Cerchia L,Comes Franchini M

更新日期：2017-05-25 00:00:00

abstract：:G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands due to the high conservation of orthosteric binding sit...

journal_title：Journal of medicinal chemistry

authors： Fronik P,Gaiser BI,Sejer Pedersen D

更新日期：2017-05-25 00:00:00

abstract：:Influenza virus (IFV) causes periodic global influenza pandemics, resulting in substantial socioeconomic loss and burden on medical facilities. Yearly variation in the effectiveness of vaccines, slow responsiveness to vaccination in cases of pandemic IFV, and emerging resistance to available drugs highlight the need t...

journal_title：Journal of medicinal chemistry

authors： Ju H,Zhang J,Huang B,Kang D,Huang B,Liu X,Zhan P

更新日期：2017-05-11 00:00:00

abstract：:A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds ...

journal_title：Journal of medicinal chemistry

authors： Qin L,Ren L,Wan S,Liu G,Luo X,Liu Z,Li F,Yu Y,Liu J,Wei Y

更新日期：2017-05-11 00:00:00

abstract：:Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromati...

journal_title：Journal of medicinal chemistry

authors： Bouché L,Christ CD,Siegel S,Fernández-Montalván AE,Holton SJ,Fedorov O,Ter Laak A,Sugawara T,Stöckigt D,Tallant C,Bennett J,Monteiro O,Díaz-Sáez L,Siejka P,Meier J,Pütter V,Weiske J,Müller S,Huber KVM,Hartung IV,H

更新日期：2017-05-11 00:00:00

abstract：:Undetected pan-assay interference compounds (PAINS) with false-positive activities in assays often propagate through medicinal chemistry programs and compromise their outcomes. Although a large number of PAINS have been classified, often on the basis of individual studies or chemical experience, little has been done s...

journal_title：Journal of medicinal chemistry

authors： Jasial S,Hu Y,Bajorath J

更新日期：2017-05-11 00:00:00

abstract：:There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens ...

journal_title：Journal of medicinal chemistry

authors： Surivet JP,Zumbrunn C,Bruyère T,Bur D,Kohl C,Locher HH,Seiler P,Ertel EA,Hess P,Enderlin-Paput M,Enderlin-Paput S,Gauvin JC,Mirre A,Hubschwerlen C,Ritz D,Rueedi G

更新日期：2017-05-11 00:00:00

abstract：:Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyrid...

journal_title：Journal of medicinal chemistry

authors： Tan L,Tao Y,Wang T,Zou F,Zhang S,Kou Q,Niu A,Chen Q,Chu W,Chen X,Wang H,Yang Y

更新日期：2017-04-13 00:00:00

abstract：:Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGF...

journal_title：Journal of medicinal chemistry

authors： Planken S,Behenna DC,Nair SK,Johnson TO,Nagata A,Almaden C,Bailey S,Ballard TE,Bernier L,Cheng H,Cho-Schultz S,Dalvie D,Deal JG,Dinh DM,Edwards MP,Ferre RA,Gajiwala KS,Hemkens M,Kania RS,Kath JC,Matthews J,Murra

更新日期：2017-04-13 00:00:00

abstract：:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with t...

journal_title：Journal of medicinal chemistry

authors： Dong Y,Wang X,Kamaraj S,Bulbule VJ,Chiu FC,Chollet J,Dhanasekaran M,Hein CD,Papastogiannidis P,Morizzi J,Shackleford DM,Barker H,Ryan E,Scheurer C,Tang Y,Zhao Q,Zhou L,White KL,Urwyler H,Charman WN,Matile H,Witt

更新日期：2017-04-13 00:00:00

abstract：:The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically a...

journal_title：Journal of medicinal chemistry

authors： Li H,Huang Q,Chen C,Xu B,Wang HY,Long YQ

更新日期：2017-04-13 00:00:00

abstract：:Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, a...

journal_title：Journal of medicinal chemistry

authors： Tichý M,Smoleń S,Tloušt'ová E,Pohl R,Oždian T,Hejtmánková K,Lišková B,Gurská S,Džubák P,Hajdúch M,Hocek M

更新日期：2017-03-23 00:00:00

abstract：:While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improv...

journal_title：Journal of medicinal chemistry

authors： Chen X,Giraldes J,Sprague ER,Shakya S,Chen Z,Wang Y,Joud C,Mathieu S,Chen CH,Straub C,Duca J,Hurov K,Yuan Y,Shao W,Touré BB

更新日期：2017-03-09 00:00:00

abstract：:Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydr...

journal_title：Journal of medicinal chemistry

authors： Lu W,Yao X,Ouyang P,Dong N,Wu D,Jiang X,Wu Z,Zhang C,Xu Z,Tang Y,Zou S,Liu M,Li J,Zeng M,Lin P,Cheng F,Huang J

更新日期：2017-03-09 00:00:00

abstract：:The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have...

journal_title：Journal of medicinal chemistry

authors： Perez C,Li J,Parlati F,Rouffet M,Ma Y,Mackinnon AL,Chou TF,Deshaies RJ,Cohen SM

更新日期：2017-02-23 00:00:00

abstract：:Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 wi...

journal_title：Journal of medicinal chemistry

authors： Nagase H,Yamamoto N,Yata M,Ohrui S,Okada T,Saitoh T,Kutsumura N,Nagumo Y,Irukayama-Tomobe Y,Ishikawa Y,Ogawa Y,Hirayama S,Kuroda D,Watanabe Y,Gouda H,Yanagisawa M

更新日期：2017-02-09 00:00:00

abstract：:The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole...

journal_title：Journal of medicinal chemistry

authors： Muth F,El-Gokha A,Ansideri F,Eitel M,Döring E,Sievers-Engler A,Lange A,Boeckler FM,Lämmerhofer M,Koch P,Laufer SA

更新日期：2017-01-26 00:00:00

abstract：:We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)]+ (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometalli...

journal_title：Journal of medicinal chemistry

authors： Zhong HJ,Wang W,Kang TS,Yan H,Yang Y,Xu L,Wang Y,Ma DL,Leung CH

更新日期：2017-01-12 00:00:00

abstract：:HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% o...

journal_title：Journal of medicinal chemistry

authors： Castro E,Martinez ZS,Seong CS,Cabrera-Espinoza A,Ruiz M,Hernandez Garcia A,Valdez F,Llano M,Echegoyen L

更新日期：2016-12-22 00:00:00

abstract：:Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore i...

journal_title：Journal of medicinal chemistry

authors： Van der Poorten O,Knuhtsen A,Sejer Pedersen D,Ballet S,Tourwé D

更新日期：2016-12-22 00:00:00

abstract：:Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending o...

journal_title：Journal of medicinal chemistry

authors： Tosh DK,Ciancetta A,Warnick E,Crane S,Gao ZG,Jacobson KA

更新日期：2016-12-22 00:00:00

abstract：:Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and s...

journal_title：Journal of medicinal chemistry

authors： Siegrist R,Pozzi D,Jacob G,Torrisi C,Colas K,Braibant B,Mawet J,Pfeifer T,de Kanter R,Roch C,Kessler M,Moon R,Corminboeuf O,Bezençon O

更新日期：2016-12-08 00:00:00

abstract：:The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in anima...

journal_title：Journal of medicinal chemistry

authors： Cao J,Slack RD,Bakare OM,Burzynski C,Rais R,Slusher BS,Kopajtic T,Bonifazi A,Ellenberger MP,Yano H,He Y,Bi GH,Xi ZX,Loland CJ,Newman AH

更新日期：2016-12-08 00:00:00

abstract：:Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds...

journal_title：Journal of medicinal chemistry

authors： Serpi M,Ferrari V,Pertusati F

更新日期：2016-12-08 00:00:00