abstract：:The N- and C-terminal domains of human somatic angiotensin I converting enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates was...

journal_title：Journal of medicinal chemistry

authors： Hocharoen L,Joyner JC,Cowan JA

更新日期：2013-12-27 00:00:00

abstract：:The limited number of drug classes licensed for treatment of influenza virus (Flu), together with the continuous emergence of viral variants and drug resistant mutants, highlights the urgent need to find antivirals with novel mechanisms of action. In this context, the viral RNA-dependent RNA polymerase (RdRP) subunits...

journal_title：Journal of medicinal chemistry

authors： Massari S,Nannetti G,Goracci L,Sancineto L,Muratore G,Sabatini S,Manfroni G,Mercorelli B,Cecchetti V,Facchini M,Palù G,Cruciani G,Loregian A,Tabarrini O

更新日期：2013-12-27 00:00:00

abstract：:We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5-10) with one-to-six bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analogue and potently inhibited proliferation of folate receptor (FR) α-expressing Chinese ha...

journal_title：Journal of medicinal chemistry

authors： Mitchell-Ryan S,Wang Y,Raghavan S,Ravindra MP,Hales E,Orr S,Cherian C,Hou Z,Matherly LH,Gangjee A

更新日期：2013-12-27 00:00:00

abstract：:In tissue engineering, survival of larger constructs remains challenging due to limited supply of oxygen caused by a lack of early vascularization. Controlled release of oxygen from small organic molecules represents a possible strategy to prevent cell death under anoxic conditions. A comprehensive study of methylated...

journal_title：Journal of medicinal chemistry

authors： Benz S,Nötzli S,Siegel JS,Eberli D,Jessen HJ

更新日期：2013-12-27 00:00:00

abstract：:Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compoun...

journal_title：Journal of medicinal chemistry

authors： Keenan M,Chaplin JH,Alexander PW,Abbott MJ,Best WM,Khong A,Botero A,Perez C,Cornwall S,Thompson RA,White KL,Shackleford DM,Koltun M,Chiu FC,Morizzi J,Ryan E,Campbell M,von Geldern TW,Scandale I,Chatelain E,Charman

更新日期：2013-12-27 00:00:00

abstract：:Nicotine binds to nicotinic acetylcholine receptors (nAChR), which can exist as many different subtypes. The α4β2 nAChR is the most prevalent subtype in the brain and possesses the most evidence linking it to nicotine seeking behavior. Herein we report the use of mixture based combinatorial libraries for the rapid dis...

journal_title：Journal of medicinal chemistry

authors： Wu J,Zhang Y,Maida LE,Santos RG,Welmaker GS,LaVoi TM,Nefzi A,Yu Y,Houghten RA,Toll L,Giulianotti MA

更新日期：2013-12-27 00:00:00

abstract：:A series of conjugated hyaluronic acid particles (HAP), composed of a hydrophobic anticancer drug core and hydrophilic cyclodextrin/hyaluronic acid shell, were prepared through self-assembling and characterized by (1)H NMR titration, electron microscopy, zeta potential, and dynamic light-scattering experiments. The na...

journal_title：Journal of medicinal chemistry

authors： Yang Y,Zhang YM,Chen Y,Chen JT,Liu Y

更新日期：2013-12-12 00:00:00

abstract：:The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described, and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the ...

journal_title：Journal of medicinal chemistry

authors： Banala AK,Zhang P,Plenge P,Cyriac G,Kopajtic T,Katz JL,Loland CJ,Newman AH

更新日期：2013-12-12 00:00:00

abstract：:Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal ce...

journal_title：Journal of medicinal chemistry

authors： Millard M,Gallagher JD,Olenyuk BZ,Neamati N

更新日期：2013-11-27 00:00:00

abstract：:Sepsis, which is a systemic inflammatory response that follows a bacterial infection, has a high mortality rate and limited therapeutic options. Here we show that the antimicrobial peptide OH-CATH30, which naturally occurs in snake, selectively regulates the innate immune response to protect mice from lethal sepsis. T...

journal_title：Journal of medicinal chemistry

authors： Li SA,Xiang Y,Wang YJ,Liu J,Lee WH,Zhang Y

更新日期：2013-11-27 00:00:00

abstract：:In this study, we developed an assignment-free approach for rapid identification of ligand-binding sites in target proteins by using NMR. With a sophisticated cell-free stable isotope-labeling procedure that introduces (15)N- or (13)C-labels to specific atoms of target proteins, this approach requires only a single se...

journal_title：Journal of medicinal chemistry

authors： Kodama Y,Takeuchi K,Shimba N,Ishikawa K,Suzuki E,Shimada I,Takahashi H

更新日期：2013-11-27 00:00:00

abstract：:Aiming to image NTS1 overexpressing tumors, the diarylpyrazole glycoconjugate 8, derived from the potent NTS1 antagonist SR142948A, was synthesized taking advantage of the palladium-catalyzed aminocarbonylation reaction. The glycoconjugate 8 displayed excellent affinity and selectivity toward NTS1. Radiosynthesis proc...

journal_title：Journal of medicinal chemistry

authors： Lang C,Maschauer S,Hübner H,Gmeiner P,Prante O

更新日期：2013-11-27 00:00:00

abstract：:On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second...

journal_title：Journal of medicinal chemistry

authors： Yuan Y,Zaidi SA,Elbegdorj O,Aschenbach LC,Li G,Stevens DL,Scoggins KL,Dewey WL,Selley DE,Zhang Y

更新日期：2013-11-27 00:00:00

abstract：:Uridine (Urd) is a promising biochemical modulator to reduce host toxicity caused by 5-fluorouracil (5-FU) without impairing its antitumor activity. Elevated doses of Urd are required to achieve a protective effect against 5-FU toxicity, but exogenous administration of Urd is not well-tolerated. Selective inhibitors o...

journal_title：Journal of medicinal chemistry

authors： Renck D,Machado P,Souto AA,Rosado LA,Erig T,Campos MM,Farias CB,Roesler R,Timmers LF,de Souza ON,Santos DS,Basso LA

更新日期：2013-11-14 00:00:00

abstract：:The synthetic chemical nuclease, [Cu(1,10-phenanthroline)2](2+), has stimulated research within metallonuclease development and in the area of cytotoxic metallodrug design. Our analysis reveals, however, that this agent is "promiscuous" as it binds both dsDNA and protein biomolecules, without specificity, and induces ...

journal_title：Journal of medicinal chemistry

authors： Prisecaru A,McKee V,Howe O,Rochford G,McCann M,Colleran J,Pour M,Barron N,Gathergood N,Kellett A

更新日期：2013-11-14 00:00:00

abstract：:A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration o...

journal_title：Journal of medicinal chemistry

authors： Kale MG,Raichurkar A,P SH,Waterson D,McKinney D,Manjunatha MR,Kranthi U,Koushik K,Jena Lk,Shinde V,Rudrapatna S,Barde S,Humnabadkar V,Madhavapeddi P,Basavarajappa H,Ghosh A,Ramya VK,Guptha S,Sharma S,Vachaspati P,

更新日期：2013-11-14 00:00:00

abstract：:A library of 3-hydroxy-2,3-dihydropyridones was synthesized, and their activities as antiandrogens were tested in the human prostate cancer cell line LNCaP. Structure-activity relationship (SAR) studies resulted in the identification of a potent compound whose activity is comparable to that of MDV3100. Homology modeli...

journal_title：Journal of medicinal chemistry

authors： Pepe A,Pamment M,Kim YS,Lee S,Lee MJ,Beebe K,Filikov A,Neckers L,Trepel JB,Malhotra SV

更新日期：2013-11-14 00:00:00

abstract：:A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on...

journal_title：Journal of medicinal chemistry

authors： Rami M,Dubois L,Parvathaneni NK,Alterio V,van Kuijk SJ,Monti SM,Lambin P,De Simone G,Supuran CT,Winum JY

更新日期：2013-11-14 00:00:00

abstract：:Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally rela...

journal_title：Journal of medicinal chemistry

authors： Cherblanc FL,Chapman KL,Reid J,Borg AJ,Sundriyal S,Alcazar-Fuoli L,Bignell E,Demetriades M,Schofield CJ,DiMaggio PA Jr,Brown R,Fuchter MJ

更新日期：2013-11-14 00:00:00

abstract：:Indoleamine 2,3-dioxygenase (IDO-1) is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. However, only a few structural classes are known to be IDO-1 inhibitors. In this study, a natural ...

journal_title：Journal of medicinal chemistry

authors： Yang S,Li X,Hu F,Li Y,Yang Y,Yan J,Kuang C,Yang Q

更新日期：2013-11-14 00:00:00

abstract：:Optimization of the pharmacokinetic properties for a series of benzoxazolone derivatives led to the identification of 9b, which showed anxiolytic effect in a rat model. However, 9b, like known benzodiazepines, induced motor impairment. Investigation into the cause of this unexpected side effect and management of 9b of...

journal_title：Journal of medicinal chemistry

authors： Fukaya T,Ishiyama T,Baba S,Masumoto S

更新日期：2013-10-24 00:00:00

abstract：:Malaria represents a significant health issue, and novel and effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. Antimalarial drug discovery has historically benefited from a whole-cell (phenotypic) screening approach to identify lead molecules. This approach has bee...

journal_title：Journal of medicinal chemistry

authors： Chatterjee AK

更新日期：2013-10-24 00:00:00

abstract：:The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIA...

journal_title：Journal of medicinal chemistry

authors： Kester RF,Donnell AF,Lou Y,Remiszewski SW,Lombardo LJ,Chen S,Le NT,Lo J,Moliterni JA,Han X,Hogg JH,Liang W,Michoud C,Rupert KC,Mischke S,Le K,Weisel M,Janson CA,Lukacs CM,Fretland AJ,Hong K,Polonskaia A,Gao L

更新日期：2013-10-24 00:00:00

abstract：:Brain metastasis occurs in 20-40% of cancer patients. Treatment is mostly palliative, and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascular...

journal_title：Journal of medicinal chemistry

authors： Gooyit M,Song W,Mahasenan KV,Lichtenwalter K,Suckow MA,Schroeder VA,Wolter WR,Mobashery S,Chang M

更新日期：2013-10-24 00:00:00

abstract：:A gadolinium complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and benzothiazole-aniline (BTA) of the type [Gd(DO3A-BTA)(H2O)] has been prepared for use as a single molecule theranostic agent. The kinetic inertness and r1 relaxivity (= 3.84 mM(-1) s(-1)) of the complex compare well with those of s...

journal_title：Journal of medicinal chemistry

authors： Kim HK,Kang MK,Jung KH,Kang SH,Kim YH,Jung JC,Lee GH,Chang Y,Kim TJ

更新日期：2013-10-24 00:00:00

abstract：:Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processe...

journal_title：Journal of medicinal chemistry

authors： Hinklin RJ,Boyd SA,Chicarelli MJ,Condroski KR,DeWolf WE Jr,Lee PA,Lee W,Singh A,Thomas L,Voegtli WC,Williams L,Aicher TD

更新日期：2013-10-10 00:00:00

abstract：:Discovery of novel effective and safe antimalarials has been traditionally focused on targeting erythrocytic parasite stages that cause clinical symptoms. However, elimination of malaria parasites from the human population will be facilitated by intervention at different life-cycle stages of the parasite, including th...

journal_title：Journal of medicinal chemistry

authors： Ressurreição AS,Gonçalves D,Sitoe AR,Albuquerque IS,Gut J,Góis A,Gonçalves LM,Bronze MR,Hanscheid T,Biagini GA,Rosenthal PJ,Prudêncio M,O'Neill P,Mota MM,Lopes F,Moreira R

更新日期：2013-10-10 00:00:00

abstract：:Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the ...

journal_title：Journal of medicinal chemistry

authors： Devasthale P,Wang Y,Wang W,Fevig J,Feng J,Wang A,Harrity T,Egan D,Morgan N,Cap M,Fura A,Klei HE,Kish K,Weigelt C,Sun L,Levesque P,Moulin F,Li YX,Zahler R,Kirby MS,Hamann LG

更新日期：2013-09-26 00:00:00

abstract：:The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is ...

journal_title：Journal of medicinal chemistry

authors： Huryn DM,Resnick LO,Wipf P

更新日期：2013-09-26 00:00:00

abstract：:Leishmaniasis is an infection provoked by protozoans belonging to the genus Leishmania. Among the many species and subsepecies of such protozoa, Leishmania donovani chagasi causes visceral leishmaniasis. A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized from this organism, denominated here LdcCA. Ld...

journal_title：Journal of medicinal chemistry

authors： Syrjänen L,Vermelho AB,Rodrigues Ide A,Corte-Real S,Salonen T,Pan P,Vullo D,Parkkila S,Capasso C,Supuran CT

更新日期：2013-09-26 00:00:00

abstract：:In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to re...

journal_title：Journal of medicinal chemistry

authors： Mellini P,Kokkola T,Suuronen T,Salo HS,Tolvanen L,Mai A,Lahtela-Kakkonen M,Jarho EM

更新日期：2013-09-12 00:00:00

abstract：:The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilin...

journal_title：Journal of medicinal chemistry

authors： Pletsas D,Garelnabi EA,Li L,Phillips RM,Wheelhouse RT

更新日期：2013-09-12 00:00:00

abstract：:Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hy...

journal_title：Journal of medicinal chemistry

authors： Yu CW,Chang PT,Hsin LW,Chern JW

更新日期：2013-09-12 00:00:00

abstract：:Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of ...

journal_title：Journal of medicinal chemistry

authors： Acker TM,Khatri A,Vance KM,Slabber C,Bacsa J,Snyder JP,Traynelis SF,Liotta DC

更新日期：2013-08-22 00:00:00

abstract：:G-Quadruplexes, noncanonical nucleic acid structures, act as silencers in the promoter regions of human genes; putative G-quadruplex forming sequences are also present in promoters of other mammals, yeasts, and prokaryotes. Here we show that also the HIV-1 LTR promoter exploits G-quadruplex-mediated transcriptional re...

journal_title：Journal of medicinal chemistry

authors： Perrone R,Nadai M,Frasson I,Poe JA,Butovskaya E,Smithgall TE,Palumbo M,Palù G,Richter SN

更新日期：2013-08-22 00:00:00

abstract：:Human neutrophil elastase (HNE) is an important therapeutic target for treatment of pulmonary diseases. Previously, we identified novel N-benzoylindazole derivatives as potent, competitive, and pseudoirreversible HNE inhibitors. Here, we report further development of these inhibitors with improved potency, protease se...

journal_title：Journal of medicinal chemistry

authors： Crocetti L,Schepetkin IA,Cilibrizzi A,Graziano A,Vergelli C,Giomi D,Khlebnikov AI,Quinn MT,Giovannoni MP

更新日期：2013-08-08 00:00:00

abstract：:We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activi...

journal_title：Journal of medicinal chemistry

authors： Johns BA,Kawasuji T,Weatherhead JG,Taishi T,Temelkoff DP,Yoshida H,Akiyama T,Taoda Y,Murai H,Kiyama R,Fuji M,Tanimoto N,Jeffrey J,Foster SA,Yoshinaga T,Seki T,Kobayashi M,Sato A,Johnson MN,Garvey EP,Fujiwara T

更新日期：2013-07-25 00:00:00

abstract：:A new series of zinc(II) phthalocyanine derivatives have been synthesized and characterized. These macrocycles exhibited a sharp absorption band in the red visible region in DMF, which indicated that they were dissolved well and almost did not aggregate in this solvent. Compared with the unsubstituted zinc(II) phthalo...

journal_title：Journal of medicinal chemistry

authors： Jia X,Yang FF,Li J,Liu JY,Xue JP

更新日期：2013-07-25 00:00:00

abstract：:In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bou...

journal_title：Journal of medicinal chemistry

authors： Hu X,Compton JR,Abdulhameed MD,Marchand CL,Robertson KL,Leary DH,Jadhav A,Hershfield JR,Wallqvist A,Friedlander AM,Legler PM

更新日期：2013-07-11 00:00:00

abstract：:The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that ...

journal_title：Journal of medicinal chemistry

authors： LaPlante SR,Carson R,Gillard J,Aubry N,Coulombe R,Bordeleau S,Bonneau P,Little M,O'Meara J,Beaulieu PL

更新日期：2013-06-27 00:00:00