abstract：:The first example of vinca derivatives 16-18 able to modulate P-glycoprotein (Pgp) efflux activity is reported. They were elaborated in two steps from vinorelbine 3 (VLN) by a modification of the velbenamine moiety. These compounds were able to decrease efficiently Pgp mediated influx and efflux of rhodamine-123 (Rho)...

journal_title：Journal of medicinal chemistry

authors： Gherbovet O,García Alvarez MC,Bignon J,Roussi F

更新日期：2016-12-08 00:00:00

abstract：:Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibite...

journal_title：Journal of medicinal chemistry

authors： Yoon S,Kim JH,Kim SE,Kim C,Tran PT,Ann J,Koh Y,Jang J,Kim S,Moon HS,Kim WK,Lee S,Lee J,Kim S,Lee J

更新日期：2016-11-23 00:00:00

abstract：:In a previous study, a cocrystal structure of PPARγ bound to 2-chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (1, T2384) revealed two orthosteric pocket binding modes attributed to a concentration-dependent biochemical activity profile. However, 1 also bound an a...

journal_title：Journal of medicinal chemistry

authors： Hughes TS,Shang J,Brust R,de Vera IMS,Fuhrmann J,Ruiz C,Cameron MD,Kamenecka TM,Kojetin DJ

更新日期：2016-11-23 00:00:00

abstract：:We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had com...

journal_title：Journal of medicinal chemistry

authors： Kim J,Woo SY,Im CY,Yoo EK,Lee S,Kim HJ,Hwang HJ,Cho JH,Lee WS,Yoon H,Kim S,Kwon OB,Hwang H,Kim KH,Jeon JH,Singh TD,Kim SW,Hwang SY,Choi HS,Lee IK,Kim SH,Jeon YH,Chin J,Cho SJ

更新日期：2016-11-23 00:00:00

abstract：:The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/prot...

journal_title：Journal of medicinal chemistry

authors： Yu W,Tong L,Hu B,Zhong B,Hao J,Ji T,Zan S,Coburn CA,Selyutin O,Chen L,Rokosz L,Agrawal S,Liu R,Curry S,McMonagle P,Ingravallo P,Asante-Appiah E,Chen S,Kozlowski JA

更新日期：2016-11-23 00:00:00

abstract：:Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and con...

journal_title：Journal of medicinal chemistry

authors： Wan WB,Seth PP

更新日期：2016-11-10 00:00:00

abstract：:The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-...

journal_title：Journal of medicinal chemistry

authors： Russell S,Rahmani R,Jones AJ,Newson HL,Neilde K,Cotillo I,Rahmani Khajouei M,Ferrins L,Qureishi S,Nguyen N,Martinez-Martinez MS,Weaver DF,Kaiser M,Riley J,Thomas J,De Rycker M,Read KD,Flematti GR,Ryan E,Tanghe S,R

更新日期：2016-11-10 00:00:00

abstract：:(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viabili...

journal_title：Journal of medicinal chemistry

authors： Olivieri M,Amata E,Vinciguerra S,Fiorito J,Giurdanella G,Drago F,Caporarello N,Prezzavento O,Arena E,Salerno L,Rescifina A,Lupo G,Anfuso CD,Marrazzo A

更新日期：2016-11-10 00:00:00

abstract：:Aminoglycosides (AGs) constitute a major family of potent and broad-spectrum antibiotics disturbing protein synthesis through binding to the A site of 16S rRNA. Decades of widespread clinical use of AGs strongly reduced their clinical efficacy through the selection of resistant bacteria. Recently, conjugation of lipop...

journal_title：Journal of medicinal chemistry

authors： Zimmermann L,Das I,Désiré J,Sautrey G,Barros R S V,El Khoury M,Mingeot-Leclercq MP,Décout JL

更新日期：2016-10-27 00:00:00

abstract：:There is currently no ideal radiotracer for imaging of protein synthesis rate (PSR) by positron emission tomography (PET). Existing fluorine-18-labeled amino acid-based radiotracers predominantly visualize amino acid transporter processes, and in many cases they are not incorporated into nascent proteins at all. Other...

journal_title：Journal of medicinal chemistry

authors： Betts HM,Milicevic Sephton S,Tong C,Awais RO,Hill PJ,Perkins AC,Aigbirhio FI

更新日期：2016-10-27 00:00:00

abstract：:The synthesis of four l-2'-deoxy-threose nucleoside phosphonates with the natural nucleobases adenine, thymine, cytosine, and guanosine has been performed. Especially the adenine containing analogue (PMDTA) was endowed with potent antiviral activity displaying an EC50 of 4.69 μM against HIV-1 and an EC50 value of 0.5 ...

journal_title：Journal of medicinal chemistry

authors： Liu C,Dumbre SG,Pannecouque C,Huang C,Ptak RG,Murray MG,De Jonghe S,Herdewijn P

更新日期：2016-10-27 00:00:00

abstract：:Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging m...

journal_title：Journal of medicinal chemistry

authors： De Marco R,Bedini A,Spampinato S,Cavina L,Pirazzoli E,Gentilucci L

更新日期：2016-10-13 00:00:00

abstract：:Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in th...

journal_title：Journal of medicinal chemistry

authors： Watterson SH,De Lucca GV,Shi Q,Langevine CM,Liu Q,Batt DG,Beaudoin Bertrand M,Gong H,Dai J,Yip S,Li P,Sun D,Wu DR,Wang C,Zhang Y,Traeger SC,Pattoli MA,Skala S,Cheng L,Obermeier MT,Vickery R,Discenza LN,D'Arien

更新日期：2016-10-13 00:00:00

abstract：:The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationsh...

journal_title：Journal of medicinal chemistry

authors： Azevedo CM,Watterson KR,Wargent ET,Hansen SV,Hudson BD,Kępczyńska MA,Dunlop J,Shimpukade B,Christiansen E,Milligan G,Stocker CJ,Ulven T

更新日期：2016-10-13 00:00:00

abstract：:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimiz...

journal_title：Journal of medicinal chemistry

authors： Nishizawa N,Takatsu Y,Kumano S,Kiba A,Ban J,Tsutsumi S,Matsui H,Matsumoto SI,Yamaguchi M,Ikeda Y,Kusaka M,Ohtaki T,Itoh F,Asami T

更新日期：2016-10-13 00:00:00

abstract：:Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with a nonsubstrate analog inhibitor. Given the active site simil...

journal_title：Journal of medicinal chemistry

authors： Luciani R,Saxena P,Surade S,Santucci M,Venturelli A,Borsari C,Marverti G,Ponterini G,Ferrari S,Blundell TL,Costi MP

更新日期：2016-10-13 00:00:00

abstract：:cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited bo...

journal_title：Journal of medicinal chemistry

authors： Li B,Wang A,Liu J,Qi Z,Liu X,Yu K,Wu H,Chen C,Hu C,Wang W,Wu J,Hu Z,Ye L,Zou F,Liu F,Wang B,Wang L,Ren T,Zhang S,Bai M,Zhang S,Liu J,Liu Q

更新日期：2016-09-22 00:00:00

abstract：:The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glio...

journal_title：Journal of medicinal chemistry

authors： Rais R,Jančařík A,Tenora L,Nedelcovych M,Alt J,Englert J,Rojas C,Le A,Elgogary A,Tan J,Monincová L,Pate K,Adams R,Ferraris D,Powell J,Majer P,Slusher BS

更新日期：2016-09-22 00:00:00

abstract：:Prevalence of drug-resistant bacteria has emerged to be one of the greatest threats in the 21st century. Herein, we report the development of a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold. These molecules display good potency against a panel of multidrug-resista...

journal_title：Journal of medicinal chemistry

authors： Teng P,Huo D,Nimmagadda A,Wu J,She F,Su M,Lin X,Yan J,Cao A,Xi C,Hu Y,Cai J

更新日期：2016-09-08 00:00:00

abstract：:The DEDDh family of exonucleases plays essential roles in DNA and RNA metabolism in all kingdoms of life. Several viral and human DEDDh exonucleases can serve as antiviral drug targets due to their critical roles in virus replication. Here using RNase T and CRN-4 as the model systems, we identify potential inhibitors ...

journal_title：Journal of medicinal chemistry

authors： Huang KW,Hsu KC,Chu LY,Yang JM,Yuan HS,Hsiao YY

更新日期：2016-09-08 00:00:00

abstract：:Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC5...

journal_title：Journal of medicinal chemistry

authors： Liu J,Zheng S,Akerstrom VL,Yuan C,Ma Y,Zhong Q,Zhang C,Zhang Q,Guo S,Ma P,Skripnikova EV,Bratton MR,Pannuti A,Miele L,Wiese TE,Wang G

更新日期：2016-09-08 00:00:00

abstract：:Naturally occurring N(ω)-hydroxy-l-arginine (NOHA, 1) is the best substrate of NO synthases (NOS). The development of stable and bioavailable prodrugs would provide a pharmacologically valuable strategy for the treatment of cardiovascular diseases that are associated with endothelial dysfunction. To improve NOHAs drug...

journal_title：Journal of medicinal chemistry

authors： Litty FA,Gudd J,Girreser U,Clement B,Schade D

更新日期：2016-09-08 00:00:00

abstract：:A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at...

journal_title：Journal of medicinal chemistry

authors： Shaw DE,Baig F,Bruce I,Chamoin S,Collingwood SP,Cross S,Dayal S,Drückes P,Furet P,Furminger V,Haggart D,Hussey M,Konstantinova I,Loren JC,Molteni V,Roberts S,Reilly J,Saunders AM,Stringer R,Sviridenko L,Thomas M,

更新日期：2016-09-08 00:00:00

abstract：:EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR i...

journal_title：Journal of medicinal chemistry

authors： Hao Y,Wang X,Zhang T,Sun D,Tong Y,Xu Y,Chen H,Tong L,Zhu L,Zhao Z,Chen Z,Ding J,Xie H,Xu Y,Li H

更新日期：2016-08-11 00:00:00

abstract：:Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based...

journal_title：Journal of medicinal chemistry

authors： Li S,Xu H,Cui S,Wu F,Zhang Y,Su M,Gong Y,Qiu S,Jiao Q,Qin C,Shan J,Zhang M,Wang J,Yin Q,Xu M,Liu X,Wang R,Zhu L,Li J,Xu Y,Jiang H,Zhao Z,Li J,Li H

更新日期：2016-07-28 00:00:00

abstract：:17β-HSD14 is a SDR enzyme able to oxidize estradiol and 5-androstenediol using NAD(+). We determined the crystal structure of this human enzyme as the holo form and as ternary complexes with estrone and with the first potent, nonsteroidal inhibitor. The structures reveal a conical, rather large and lipophilic binding ...

journal_title：Journal of medicinal chemistry

authors： Bertoletti N,Braun F,Lepage M,Möller G,Adamski J,Heine A,Klebe G,Marchais-Oberwinkler S

更新日期：2016-07-28 00:00:00

abstract：:A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies...

journal_title：Journal of medicinal chemistry

authors： Morales P,Gómez-Cañas M,Navarro G,Hurst DP,Carrillo-Salinas FJ,Lagartera L,Pazos R,Goya P,Reggio PH,Guaza C,Franco R,Fernández-Ruiz J,Jagerovic N

更新日期：2016-07-28 00:00:00

abstract：:In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic sta...

journal_title：Journal of medicinal chemistry

authors： Pitta E,Rogacki MK,Balabon O,Huss S,Cunningham F,Lopez-Roman EM,Joossens J,Augustyns K,Ballell L,Bates RH,Van der Veken P

更新日期：2016-07-28 00:00:00

abstract：:The modulation of the endocannabinoid system is emerging as a viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neur...

journal_title：Journal of medicinal chemistry

authors： Montanari S,Scalvini L,Bartolini M,Belluti F,Gobbi S,Andrisano V,Ligresti A,Di Marzo V,Rivara S,Mor M,Bisi A,Rampa A

更新日期：2016-07-14 00:00:00

abstract：:New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activ...

journal_title：Journal of medicinal chemistry

authors： Vidadala RS,Rivas KL,Ojo KK,Hulverson MA,Zambriski JA,Bruzual I,Schultz TL,Huang W,Zhang Z,Scheele S,DeRocher AE,Choi R,Barrett LK,Siddaramaiah LK,Hol WG,Fan E,Merritt EA,Parsons M,Freiberg G,Marsh K,Kempf DJ,Ca

更新日期：2016-07-14 00:00:00

abstract：:Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters, and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be ...

journal_title：Journal of medicinal chemistry

authors： Neidle S

更新日期：2016-07-14 00:00:00

abstract：:UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model ...

journal_title：Journal of medicinal chemistry

authors： Junker A,Balasubramanian R,Ciancetta A,Uliassi E,Kiselev E,Martiriggiano C,Trujillo K,Mtchedlidze G,Birdwell L,Brown KA,Harden TK,Jacobson KA

更新日期：2016-07-14 00:00:00

abstract：:We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer's disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca(2+) channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatase...

journal_title：Journal of medicinal chemistry

authors： Lajarín-Cuesta R,Nanclares C,Arranz-Tagarro JA,González-Lafuente L,Arribas RL,Araujo de Brito M,Gandía L,de Los Ríos C

更新日期：2016-07-14 00:00:00

abstract：:Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tubercu...

journal_title：Journal of medicinal chemistry

authors： Yu M,Nagalingam G,Ellis S,Martinez E,Sintchenko V,Spain M,Rutledge PJ,Todd MH,Triccas JA

更新日期：2016-06-23 00:00:00

abstract：:Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human ...

journal_title：Journal of medicinal chemistry

authors： Bijelic A,Theiner S,Keppler BK,Rompel A

更新日期：2016-06-23 00:00:00

abstract：:The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, res...

journal_title：Journal of medicinal chemistry

authors： Blake JF,Burkard M,Chan J,Chen H,Chou KJ,Diaz D,Dudley DA,Gaudino JJ,Gould SE,Grina J,Hunsaker T,Liu L,Martinson M,Moreno D,Mueller L,Orr C,Pacheco P,Qin A,Rasor K,Ren L,Robarge K,Shahidi-Latham S,Stults J,S

更新日期：2016-06-23 00:00:00

abstract：:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis and limited therapeutic options. Therefore, there is an urgent need to identify new, safe, and targeted therapeutics for effective treatment of late as well as early stage disease. Plectin-1 (Plec-1) was recently identified as specifi...

journal_title：Journal of medicinal chemistry

authors： Sanna V,Nurra S,Pala N,Marceddu S,Pathania D,Neamati N,Sechi M

更新日期：2016-06-09 00:00:00

abstract：:Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery...

journal_title：Journal of medicinal chemistry

authors： Walji AM,Hostetler ED,Selnick H,Zeng Z,Miller P,Bennacef I,Salinas C,Connolly B,Gantert L,Holahan M,O'Malley S,Purcell M,Riffel K,Li J,Balsells J,OBrien JA,Melquist S,Soriano A,Zhang X,Ogawa A,Xu S,Joshi E,Del

更新日期：2016-05-26 00:00:00

abstract：:Antivirulence strategies are now attracting interest for the inherent mechanism of action advantages. In our previous work, diapophytoene desaturase (CrtN) was identified to be an attractive and drugable target for fighting pigmented S. aureus infections. In this research, we developed a series of effective benzocyclo...

journal_title：Journal of medicinal chemistry

authors： Wang Y,Di H,Chen F,Xu Y,Xiao Q,Wang X,Wei H,Lu Y,Zhang L,Zhu J,Lan L,Li J

更新日期：2016-05-26 00:00:00

abstract：:Sepsis is characterized by a systemic inflammatory response syndrome. Derivatives of indole have been reported to exhibit diverse biological activities. This study reports on the design and synthesis of a new series of indole-2-carboxamide derivatives, which are screened for their anti-inflammatory activities in RAW 2...

journal_title：Journal of medicinal chemistry

authors： Liu Z,Tang L,Zhu H,Xu T,Qiu C,Zheng S,Gu Y,Feng J,Zhang Y,Liang G

更新日期：2016-05-26 00:00:00