Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.

abstract：:The limited efficacy and considerable side effects of currently available therapies for the treatment of hepatitis C virus (HCV) infection have prompted significant efforts toward the development of safe and effective new therapeutics. The pentapeptide alpha-ketoamides of type 1 were weak HCV inhibitors with a binding...

journal_title：Journal of medicinal chemistry

authors： Chen KX,Njoroge FG,Pichardo J,Prongay A,Butkiewicz N,Yao N,Madison V,Girijavallabhan V

更新日期：2005-10-06 00:00:00

abstract：:A series of new spiroglumide amido acid derivatives was synthesized and evaluated for their ability to inhibit the binding of cholecystokinin (CCK) to guinea pig brain cortex (CCKB receptors) and peripheral rat pancreatic acini (CCKA receptors), as well as to inhibit in vitro the gastrin-induced Ca2+ increase in rabbi...

journal_title：Journal of medicinal chemistry

authors： Makovec F,Peris W,Frigerio S,Giovanetti R,Letari O,Mennuni L,Revel L

更新日期：1996-01-05 00:00:00

abstract：:The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr(1)-cyclo(d-Asp(5),Dap(8))]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure-act...

journal_title：Journal of medicinal chemistry

authors： Joshi AA,Murray TF,Aldrich JV

更新日期：2015-11-25 00:00:00

abstract：:Previously reported 2-(hydroxymethyl)indoloquinones, prepared as their acetates or carbamates, were less active than 2-methyl analogues in bacterial cultures and they had no activity in mice, despite functionality appropriate for DNA cross-linking. On the basis of the hypothesis that these compounds might have been to...

journal_title：Journal of medicinal chemistry

authors： Iyengar BS,Remers WA,Catino JJ

更新日期：1989-08-01 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：:Thyroid hormone analogues, polychlorinated biphenyls (PCBs), and their derivatives were shown to bind specifically to thyroxine-specific binding sites in rat liver nuclear extracts. The structure-binding relationship for thyroxine binding prealbumin was qualitatively similar to that for the nuclear receptor. In genera...

journal_title：Journal of medicinal chemistry

authors： McKinney J,Fannin R,Jordan S,Chae K,Rickenbacher U,Pedersen L

更新日期：1987-01-01 00:00:00

abstract：:Certain phenylalkylamine derivatives have been considered to bind selectively at 5-HT2 serotonin receptors. It is now recognized that the most widely used derivatives, i.e., 1-(2,5-dimethoxy-4-X-phenyl)-2-aminopropanes where X = Me (DOM), Br (DOB), and I (DOI) (1-3, respectively) also bind at the more recently identif...

journal_title：Journal of medicinal chemistry

authors： Glennon RA,Raghupathi R,Bartyzel P,Teitler M,Leonhardt S

更新日期：1992-02-21 00:00:00

abstract：:Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most p...

journal_title：Journal of medicinal chemistry

authors： Liu F,Barsyte-Lovejoy D,Allali-Hassani A,He Y,Herold JM,Chen X,Yates CM,Frye SV,Brown PJ,Huang J,Vedadi M,Arrowsmith CH,Jin J

更新日期：2011-09-08 00:00:00

abstract：:4,4-Ditritio-(-)-nicotine (5) of high specific activity (4.7 Ci/mmol) has been synthesized from (-)-nicotine via the readily prepared 4,4-dibromocotinine (3). Scatchard analysis of the binding of 5 to the crude mitochondrial fraction of whole rat brain revealed a Ka of 4.7 X 10(6) M-1 and 13 fmol of binding sites/mg o...

journal_title：Journal of medicinal chemistry

authors： Vincek WC,Martin BR,Aceto MD,Bowman ER

更新日期：1980-08-01 00:00:00

abstract：:Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH(2)) (analogue 1, PTR 3173) that possess...

journal_title：Journal of medicinal chemistry

authors： Gazal S,Gelerman G,Ziv O,Karpov O,Litman P,Bracha M,Afargan M,Gilon C

更新日期：2002-04-11 00:00:00

abstract：:A primary goal of lead optimization is to identify compounds with improved absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A number of reports have linked computed molecular properties to desirable in vivo ADMET outcomes, but a significant limitation of these analyses is the failure t...

journal_title：Journal of medicinal chemistry

authors： Sutherland JJ,Raymond JW,Stevens JL,Baker TK,Watson DE

更新日期：2012-07-26 00:00:00

abstract：:We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT(3) receptor ligands bearing an extra basic moiety on the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not in...

journal_title：Journal of medicinal chemistry

authors： Butini S,Budriesi R,Hamon M,Morelli E,Gemma S,Brindisi M,Borrelli G,Novellino E,Fiorini I,Ioan P,Chiarini A,Cagnotto A,Mennini T,Fracasso C,Caccia S,Campiani G

更新日期：2009-11-12 00:00:00

abstract：:The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induce...

journal_title：Journal of medicinal chemistry

authors： Eda M,Takemoto T,Ono S,Okada T,Kosaka K,Gohda M,Matzno S,Nakamura N,Fukaya C

更新日期：1994-06-24 00:00:00

abstract：:Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. One of the hardest challenges in kinase inhibitor design is achieving target selectivity. By utilizing X-ray structural information for four promiscuous inhibitors, we prop...

journal_title：Journal of medicinal chemistry

authors： Aronov AM,Murcko MA

更新日期：2004-11-04 00:00:00

abstract：:C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of...

journal_title：Journal of medicinal chemistry

authors： Zhao H,Serby MD,Xin Z,Szczepankiewicz BG,Liu M,Kosogof C,Liu B,Nelson LT,Johnson EF,Wang S,Pederson T,Gum RJ,Clampit JE,Haasch DL,Abad-Zapatero C,Fry EH,Rondinone C,Trevillyan JM,Sham HL,Liu G

更新日期：2006-07-27 00:00:00

abstract：:The design, synthesis, and biological evaluation of a new class of inhibitors of thymidylate synthase (TS) is described. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures. At the onset of this project, we focused on the folate cofactor binding site of a high-re...

journal_title：Journal of medicinal chemistry

authors： Webber SE,Bleckman TM,Attard J,Deal JG,Kathardekar V,Welsh KM,Webber S,Janson CA,Matthews DA,Smith WW

更新日期：1993-03-19 00:00:00

abstract：:Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activitie...

journal_title：Journal of medicinal chemistry

authors： Chen Z,Wu Y,Liu Y,Yang S,Chen Y,Lai L

更新日期：2011-05-26 00:00:00

abstract：:Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibi...

journal_title：Journal of medicinal chemistry

authors： Pearce BC,Parker RA,Deason ME,Dischino DD,Gillespie E,Qureshi AA,Volk K,Wright JJ

更新日期：1994-02-18 00:00:00

abstract：:Previous SAR studies (Part 1: Mai, A.; et al. J. Med. Chem. 2003, 46, 512-524) performed on some portions (pyrrole-C4, pyrrole-N1, and hydroxamate group) of 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1a) highlighted its 4-phenylacetyl (1b) and 4-cynnamoyl (1c) analogues as more potent compounds in ...

journal_title：Journal of medicinal chemistry

authors： Mai A,Massa S,Cerbara I,Valente S,Ragno R,Bottoni P,Scatena R,Loidl P,Brosch G

更新日期：2004-02-26 00:00:00

abstract：:The 5-HT(6) receptor (5-HT(6)R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT(6)R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfon...

journal_title：Journal of medicinal chemistry

authors： van Loevezijn A,Venhorst J,Iwema Bakker WI,de Korte CG,de Looff W,Verhoog S,van Wees JW,van Hoeve M,van de Woestijne RP,van der Neut MA,Borst AJ,van Dongen MJ,de Bruin NM,Keizer HG,Kruse CG

更新日期：2011-10-27 00:00:00

abstract：:Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid ...

journal_title：Journal of medicinal chemistry

authors： Van Zandt MC,Jones ML,Gunn DE,Geraci LS,Jones JH,Sawicki DR,Sredy J,Jacot JL,Dicioccio AT,Petrova T,Mitschler A,Podjarny AD

更新日期：2005-05-05 00:00:00

abstract：:Syntheses of the decapeptide luteinizing hormone-releasing hormone, less thanGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 are described. The basic properties of arginine can provide a simple repetitive isolation procedure for arginine-containing peptides. The biological activities of the decapeptide, of a range of frag...

journal_title：Journal of medicinal chemistry

authors： Schafer DJ,Black AD,Bower JD

更新日期：1975-06-01 00:00:00

abstract：:Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the developmen...

journal_title：Journal of medicinal chemistry

authors： Maduskuie TP Jr,Wilde RG,Billheimer JT,Cromley DA,Germain S,Gillies PJ,Higley CA,Johnson AL,Pennev P,Shimshick EJ

更新日期：1995-03-31 00:00:00

abstract：:Quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) have been applied to elucidate the mechanisms of genotoxicity (SOSIP) of nitrofuran derivatives on Escherichia coli PQ37. The following equation was developed: log SOSIP = -33.1qc2 + 1.00 log P - 1.50Isat - 1.19MR - 0....

journal_title：Journal of medicinal chemistry

authors： Debnath AK,Hansch C,Kim KH,Martin YC

更新日期：1993-04-16 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：:We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values...

journal_title：Journal of medicinal chemistry

authors： Sanders JM,Gómez AO,Mao J,Meints GA,Van Brussel EM,Burzynska A,Kafarski P,González-Pacanowska D,Oldfield E

更新日期：2003-11-20 00:00:00

abstract：:A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could...

journal_title：Journal of medicinal chemistry

authors： Vu CB,Bemis JE,Disch JS,Ng PY,Nunes JJ,Milne JC,Carney DP,Lynch AV,Smith JJ,Lavu S,Lambert PD,Gagne DJ,Jirousek MR,Schenk S,Olefsky JM,Perni RB

更新日期：2009-03-12 00:00:00

abstract：:We explore the significance of pi-cation interactions in the binding of ligands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the interaction of aromatic amino acid side chains with the cation-containing heterocyclic ring fragmen...

journal_title：Journal of medicinal chemistry

authors： Schmitt JD,Sharples CG,Caldwell WS

更新日期：1999-08-12 00:00:00

abstract：:High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent tha...

journal_title：Journal of medicinal chemistry

authors： Duplantier AJ,Andresen CJ,Cheng JB,Cohan VL,Decker C,DiCapua FM,Kraus KG,Johnson KL,Turner CR,UmLand JP,Watson JW,Wester RT,Williams AS,Williams JA

更新日期：1998-06-18 00:00:00

abstract：:A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial act...

journal_title：Journal of medicinal chemistry

authors： Kiely JS,Hutt MP,Culbertson TP,Bucsh RA,Worth DF,Lesheski LE,Gogliotti RD,Sesnie JC,Solomon M,Mich TF

更新日期：1991-02-01 00:00:00