abstract：:The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We h...

journal_title：Journal of medicinal chemistry

authors： Burch JD,Barrett K,Chen Y,DeVoss J,Eigenbrot C,Goldsmith R,Ismaili MH,Lau K,Lin Z,Ortwine DF,Zarrin AA,McEwan PA,Barker JJ,Ellebrandt C,Kordt D,Stein DB,Wang X,Chen Y,Hu B,Xu X,Yuen PW,Zhang Y,Pei Z

更新日期：2015-05-14 00:00:00

abstract：:New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-r...

journal_title：Journal of medicinal chemistry

authors： Beltramo M,Robert V,Galibert M,Madinier JB,Marceau P,Dardente H,Decourt C,De Roux N,Lomet D,Delmas AF,Caraty A,Aucagne V

更新日期：2015-04-23 00:00:00

abstract：:Resistance to β-lactam antibiotics can be mediated by metallo-β-lactamase enzymes (MBLs). An MBL inhibitor could restore the effectiveness of β-lactams. We report on the evaluation of approved thiol-containing drugs as inhibitors of NDM-1, VIM-1, and IMP-7. Drugs were assessed by a novel assay using a purchasable fluo...

journal_title：Journal of medicinal chemistry

authors： Klingler FM,Wichelhaus TA,Frank D,Cuesta-Bernal J,El-Delik J,Müller HF,Sjuts H,Göttig S,Koenigs A,Pos KM,Pogoryelov D,Proschak E

更新日期：2015-04-23 00:00:00

abstract：:Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activi...

journal_title：Journal of medicinal chemistry

authors： Salo-Ahen OM,Tochowicz A,Pozzi C,Cardinale D,Ferrari S,Boum Y,Mangani S,Stroud RM,Saxena P,Myllykallio H,Costi MP,Ponterini G,Wade RC

更新日期：2015-04-23 00:00:00

abstract：:A series of novel β-carboline-based N-heterocyclic carbenes was prepared via Mannich reaction between methyl 1-(dimethoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate, formaldehyde, and primary amines. All compounds were evaluated for their antiproliferative activity using human breast cancer and lung cancer cell lines...

journal_title：Journal of medicinal chemistry

authors： Dighe SU,Khan S,Soni I,Jain P,Shukla S,Yadav R,Sen P,Meeran SM,Batra S

更新日期：2015-04-23 00:00:00

abstract：:In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in...

journal_title：Journal of medicinal chemistry

authors： Rochais C,Lecoutey C,Gaven F,Giannoni P,Hamidouche K,Hedou D,Dubost E,Genest D,Yahiaoui S,Freret T,Bouet V,Dauphin F,Sopkova de Oliveira Santos J,Ballandonne C,Corvaisier S,Malzert-Fréon A,Legay R,Boulouard M,Claeysen

更新日期：2015-04-09 00:00:00

abstract：:A new paradigm for drug research has emerged, namely the deliberate search for molecules able to selectively affect the proliferation, differentiation, and migration of adult stem cells within the tissues in which they exist. Recently, there has been significant interest in medicinal chemistry toward the discovery and...

journal_title：Journal of medicinal chemistry

authors： Davies SG,Kennewell PD,Russell AJ,Seden PT,Westwood R,Wynne GM

更新日期：2015-04-09 00:00:00

abstract：:The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major chal...

journal_title：Journal of medicinal chemistry

authors： Rankovic Z

更新日期：2015-03-26 00:00:00

abstract：:The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper,...

journal_title：Journal of medicinal chemistry

authors： Butler CR,Brodney MA,Beck EM,Barreiro G,Nolan CE,Pan F,Vajdos F,Parris K,Varghese AH,Helal CJ,Lira R,Doran SD,Riddell DR,Buzon LM,Dutra JK,Martinez-Alsina LA,Ogilvie K,Murray JC,Young JM,Atchison K,Robshaw A,Gon

更新日期：2015-03-26 00:00:00

abstract：:Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular prun...

journal_title：Journal of medicinal chemistry

authors： Milite C,Feoli A,Sasaki K,La Pietra V,Balzano AL,Marinelli L,Mai A,Novellino E,Castellano S,Tosco A,Sbardella G

更新日期：2015-03-26 00:00:00

abstract：:The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants of HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. The NNRTIs bind in an allosteric pocket in RT ∼10 Å away from the active site. Earlier analogues of the catechol diether compound series have picomol...

journal_title：Journal of medicinal chemistry

authors： Frey KM,Puleo DE,Spasov KA,Bollini M,Jorgensen WL,Anderson KS

更新日期：2015-03-26 00:00:00

abstract：:Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective inhibitors as chemical biology tools and ultimately as new therapeutic a...

journal_title：Journal of medicinal chemistry

authors： Lin X,Chen W,Qiu Z,Guo L,Zhu W,Li W,Wang Z,Zhang W,Zhang Z,Rong Y,Zhang M,Yu L,Zhong S,Zhao R,Wu X,Wong JC,Tang G

更新日期：2015-03-26 00:00:00

abstract：:A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy as...

journal_title：Journal of medicinal chemistry

authors： Chantigny YA,Murray JC,Kleinman EF,Robinson RP,Plotkin MA,Reese MR,Buckbinder L,McNiff PA,Millham ML,Schaefer JF,Abramov YA,Bordner J

更新日期：2015-03-26 00:00:00

abstract：:Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response. ...

journal_title：Journal of medicinal chemistry

authors： Kettle JG,Ballard P,Bardelle C,Cockerill M,Colclough N,Critchlow SE,Debreczeni J,Fairley G,Fillery S,Graham MA,Goodwin L,Guichard S,Hudson K,Ward RA,Whittaker D

更新日期：2015-03-26 00:00:00

abstract：:c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo...

journal_title：Journal of medicinal chemistry

authors： Ma Y,Sun G,Chen D,Peng X,Chen YL,Su Y,Ji Y,Liang J,Wang X,Chen L,Ding J,Xiong B,Ai J,Geng M,Shen J

更新日期：2015-03-12 00:00:00

abstract：:From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable t...

journal_title：Journal of medicinal chemistry

authors： Ratni H,Rogers-Evans M,Bissantz C,Grundschober C,Moreau JL,Schuler F,Fischer H,Alvarez Sanchez R,Schnider P

更新日期：2015-03-12 00:00:00

abstract：:Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-PET radiotracer (1) or a fluorescence probe (2) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of 2 in biotin-receptor positive (BR+) canc...

journal_title：Journal of medicinal chemistry

authors： Vineberg JG,Wang T,Zuniga ES,Ojima I

更新日期：2015-03-12 00:00:00

abstract：:High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identify...

journal_title：Journal of medicinal chemistry

authors： Pike KG,Morris J,Ruston L,Pass SL,Greenwood R,Williams EJ,Demeritt J,Culshaw JD,Gill K,Pass M,Finlay MR,Good CJ,Roberts CA,Currie GS,Blades K,Eden JM,Pearson SE

更新日期：2015-03-12 00:00:00

abstract：:Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However...

journal_title：Journal of medicinal chemistry

authors： Brücher K,Gräwert T,Konzuch S,Held J,Lienau C,Behrendt C,Illarionov B,Maes L,Bacher A,Wittlin S,Mordmüller B,Fischer M,Kurz T

更新日期：2015-02-26 00:00:00

abstract：:The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most pote...

journal_title：Journal of medicinal chemistry

authors： Mbatia HW,Ramalingam S,Ramamurthy VP,Martin MS,Kwegyir-Afful AK,Njar VC

更新日期：2015-02-26 00:00:00

abstract：:The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and pot...

journal_title：Journal of medicinal chemistry

authors： Takahashi H,Riether D,Bartolozzi A,Bosanac T,Berger V,Binetti R,Broadwater J,Chen Z,Crux R,De Lombaert S,Dave R,Dines JA,Fadra-Khan T,Flegg A,Garrigou M,Hao MH,Huber J,Hutzler JM,Kerr S,Kotey A,Liu W,Lo HY,Lok

更新日期：2015-02-26 00:00:00

abstract：:Polynuclear Pt(II) complexes are a novel class of promising anticancer agents with potential clinical significance. A series of pyrazine (pz) bridged dinuclear Pt(II) complexes with general formulas {[Pt(L)Cl]2(μ-pz)}(2+) (L, ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2...

journal_title：Journal of medicinal chemistry

authors： Senerovic L,Zivkovic MD,Veselinovic A,Pavic A,Djuran MI,Rajkovic S,Nikodinovic-Runic J

更新日期：2015-02-12 00:00:00

abstract：:Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase...

journal_title：Journal of medicinal chemistry

authors： Zhao Y,Aguilar A,Bernard D,Wang S

更新日期：2015-02-12 00:00:00

abstract：:Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition o...

journal_title：Journal of medicinal chemistry

authors： Wu CH,Wang CJ,Chang CP,Cheng YC,Song JS,Jan JJ,Chou MC,Ke YY,Ma J,Wong YC,Hsieh TC,Tien YC,Gullen EA,Lo CF,Cheng CY,Liu YW,Sadani AA,Tsai CH,Hsieh HP,Tsou LK,Shia KS

更新日期：2015-02-12 00:00:00

abstract：:Nintedanib (BIBF1120) is a potent, oral, small-molecule tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor rece...

journal_title：Journal of medicinal chemistry

authors： Roth GJ,Binder R,Colbatzky F,Dallinger C,Schlenker-Herceg R,Hilberg F,Wollin SL,Kaiser R

更新日期：2015-02-12 00:00:00

abstract：:Protein arginine methyltransferase 1 (PRMT1) is involved in many biological activities, such as gene transcription, signal transduction, and RNA processing. Overexpression of PRMT1 is related to cardiovascular diseases, kidney diseases, and cancers; therefore, selective PRMT1 inhibitors serve as chemical probes to inv...

journal_title：Journal of medicinal chemistry

authors： Hu H,Owens EA,Su H,Yan L,Levitz A,Zhao X,Henary M,Zheng YG

更新日期：2015-02-12 00:00:00

abstract：:We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (-)-Δ(8)-THC analogues encompassing a carboxye...

journal_title：Journal of medicinal chemistry

authors： Nikas SP,Sharma R,Paronis CA,Kulkarni S,Thakur GA,Hurst D,Wood JT,Gifford RS,Rajarshi G,Liu Y,Raghav JG,Guo JJ,Järbe TU,Reggio PH,Bergman J,Makriyannis A

更新日期：2015-01-22 00:00:00

abstract：:Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge becaus...

journal_title：Journal of medicinal chemistry

authors： Holden JK,Kang S,Hollingsworth SA,Li H,Lim N,Chen S,Huang H,Xue F,Tang W,Silverman RB,Poulos TL

更新日期：2015-01-22 00:00:00

abstract：:Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which afte...

journal_title：Journal of medicinal chemistry

authors： Boztaş M,Çetinkaya Y,Topal M,Gülçin İ,Menzek A,Şahin E,Tanc M,Supuran CT

更新日期：2015-01-22 00:00:00

abstract：:Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compoun...

journal_title：Journal of medicinal chemistry

authors： Koh JJ,Lin S,Aung TT,Lim F,Zou H,Bai Y,Li J,Lin H,Pang LM,Koh WL,Salleh SM,Lakshminarayanan R,Zhou L,Qiu S,Pervushin K,Verma C,Tan DT,Cao D,Liu S,Beuerman RW

更新日期：2015-01-22 00:00:00

abstract：:Intrigued by the role of protein acetylation in hepatitis C virus (HCV) replication, we tested known histone deacetylase (HDAC) inhibitors and a focused library of structurally simple hydroxamic acids for inhibition of a HCV subgenomic replicon. While known HDAC inhibitors with varied inhibitory profiles proved to be ...

journal_title：Journal of medicinal chemistry

authors： Ai T,Xu Y,Qiu L,Geraghty RJ,Chen L

更新日期：2015-01-22 00:00:00

abstract：:We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacolo...

journal_title：Journal of medicinal chemistry

authors： Kelly B,McMullan M,Muguruza C,Ortega JE,Meana JJ,Callado LF,Rozas I

更新日期：2015-01-22 00:00:00

abstract：:Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, c...

journal_title：Journal of medicinal chemistry

authors： Gorham RD Jr,Forest DL,Khoury GA,Smadbeck J,Beecher CN,Healy ED,Tamamis P,Archontis G,Larive CK,Floudas CA,Radeke MJ,Johnson LV,Morikis D

更新日期：2015-01-22 00:00:00

abstract：:The scaffold concept was applied to systematically determine, analyze, and compare core structures of kinase inhibitors. From publicly available inhibitors of the human kinome, scaffolds and cyclic skeletons were systematically extracted and organized taking activity data, structural relationships, and retrosynthetic ...

journal_title：Journal of medicinal chemistry

authors： Hu Y,Bajorath J

更新日期：2015-01-08 00:00:00

abstract：:Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially use...

journal_title：Journal of medicinal chemistry

authors： Henderson JL,Kormos BL,Hayward MM,Coffman KJ,Jasti J,Kurumbail RG,Wager TT,Verhoest PR,Noell GS,Chen Y,Needle E,Berger Z,Steyn SJ,Houle C,Hirst WD,Galatsis P

更新日期：2015-01-08 00:00:00

abstract：:Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this l...

journal_title：Journal of medicinal chemistry

authors： Pasquier B,El-Ahmad Y,Filoche-Rommé B,Dureuil C,Fassy F,Abecassis PY,Mathieu M,Bertrand T,Benard T,Barrière C,El Batti S,Letallec JP,Sonnefraud V,Brollo M,Delbarre L,Loyau V,Pilorge F,Bertin L,Richepin P,Arigon J,

更新日期：2015-01-08 00:00:00

abstract：:Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previous...

journal_title：Journal of medicinal chemistry

authors： Qin J,Rajaratnam R,Feng L,Salami J,Barber-Rotenberg JS,Domsic J,Reyes-Uribe P,Liu H,Dang W,Berger SL,Villanueva J,Meggers E,Marmorstein R

更新日期：2015-01-08 00:00:00

abstract：:Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding m...

journal_title：Journal of medicinal chemistry

authors： Patel S,Cohen F,Dean BJ,De La Torre K,Deshmukh G,Estrada AA,Ghosh AS,Gibbons P,Gustafson A,Huestis MP,Le Pichon CE,Lin H,Liu W,Liu X,Liu Y,Ly CQ,Lyssikatos JP,Ma C,Scearce-Levie K,Shin YG,Solanoy H,Stark KL,Wa

更新日期：2015-01-08 00:00:00

abstract：:Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we des...

journal_title：Journal of medicinal chemistry

authors： Cocco M,Garella D,Di Stilo A,Borretto E,Stevanato L,Giorgis M,Marini E,Fantozzi R,Miglio G,Bertinaria M

更新日期：2014-12-26 00:00:00

abstract：:The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold ...

journal_title：Journal of medicinal chemistry

authors： Lan Y,Chen Y,Cao X,Zhang J,Wang J,Xu X,Qiu Y,Zhang T,Liu X,Liu BF,Zhang G

更新日期：2014-12-26 00:00:00