Selectivity determinants of inhibitor binding to human 20alpha-hydroxysteroid dehydrogenase: crystal structure of the enzyme in ternary complex with coenzyme and the potent inhibitor 3,5-dichlorosalicylic acid.

abstract：:Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective...

journal_title：Journal of medicinal chemistry

authors： Vougogiannopoulou K,Ferandin Y,Bettayeb K,Myrianthopoulos V,Lozach O,Fan Y,Johnson CH,Magiatis P,Skaltsounis AL,Mikros E,Meijer L

更新日期：2008-10-23 00:00:00

abstract：:With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the ...

journal_title：Journal of medicinal chemistry

authors： Yu Q,Holloway HW,Flippen-Anderson JL,Hoffman B,Brossi A,Greig NH

更新日期：2001-11-22 00:00:00

abstract：:Starting with 2,6-dichlorophenyl isothiocyanate, 1-(2-aminoethyl)-2-cyano-3-(2,6-dichlorophenyl)guanidine (2) was prepared in three steps. In contrast to the corresponding thiourea 1, this compound was essentially inactive as an antihypertensive agent. ...

journal_title：Journal of medicinal chemistry

authors： Tilley JW,Ramuz H,Hefti F,Gerold M

更新日期：1980-12-01 00:00:00

abstract：:Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-penta...

journal_title：Journal of medicinal chemistry

authors： Yamada S,Kawasaki M,Fujihara M,Watanabe M,Takamura Y,Takioku M,Nishioka H,Takeuchi Y,Makishima M,Motoyama T,Ito S,Tokiwa H,Nakano S,Kakuta H

更新日期：2019-10-10 00:00:00

abstract：:The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and s...

journal_title：Journal of medicinal chemistry

authors： Dhanya RP,Sidique S,Sheffler DJ,Nickols HH,Herath A,Yang L,Dahl R,Ardecky R,Semenova S,Markou A,Conn PJ,Cosford ND

更新日期：2011-01-13 00:00:00

abstract：:The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding en...

journal_title：Journal of medicinal chemistry

authors： Bertha CM,Mattson MV,Flippen-Anderson JL,Rothman RB,Xu H,Cha XY,Becketts K,Rice KC

更新日期：1994-09-16 00:00:00

abstract：:Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford va...

journal_title：Journal of medicinal chemistry

authors： Choo H,Chen X,Yadav V,Wang J,Schinazi RF,Chu CK

更新日期：2006-03-09 00:00:00

abstract：:In this work, we introduce a four-step scoring and filtering procedure, furnishing target specific virtual screening (TS-VS), which serves to minimize false positives resulting from conformational artifacts of the docking process and is optimized to converge on novel chemotypes of estrogen receptor alpha (ERalpha). As...

journal_title：Journal of medicinal chemistry

authors： Knox AJ,Meegan MJ,Sobolev V,Frost D,Zisterer DM,Williams DC,Lloyd DG

更新日期：2007-11-01 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：:An approach to the development of new anticandidal drugs is described that employs peptides as carriers of toxic agents into cells. 5-Flurorcytosine (5-FC) was chosen as a toxic agent with which to prepare 5-FC-peptide conjugates as models to test the carrier proposal. Model compounds were synthesized and then tested ...

journal_title：Journal of medicinal chemistry

authors： Steinfeld AS,Naider F,Becker JM

更新日期：1979-09-01 00:00:00

abstract：:Sansalvamide A, a cyclic depsipeptide isolated from a marine fungus of the genus Fusarium, is composed of four hydrophobic amino acids (Phe, two Leu, Val) and one hydroxy acid ((S)-2-hydroxy-4-methylpentanoic acid; O-Leu) with five stereogenic centers all having S-stereochemistry. We have recently synthesized the corr...

journal_title：Journal of medicinal chemistry

authors： Liu S,Gu W,Lo D,Ding XZ,Ujiki M,Adrian TE,Soff GA,Silverman RB

更新日期：2005-05-19 00:00:00

abstract：:SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to ...

journal_title：Journal of medicinal chemistry

authors： Geronikaki A,Eleftheriou P,Vicini P,Alam I,Dixit A,Saxena AK

更新日期：2008-09-11 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：:Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochemical characterization of a 6X protease mutant arising from in vitro selection with compound 1, a C 2-symmetric diol protease inhibitor, has been previously des...

journal_title：Journal of medicinal chemistry

authors： Giffin MJ,Heaslet H,Brik A,Lin YC,Cauvi G,Wong CH,McRee DE,Elder JH,Stout CD,Torbett BE

更新日期：2008-10-23 00:00:00

abstract：:Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the...

journal_title：Journal of medicinal chemistry

authors： Razdan RK,Terris BZ,Pars HG,Plotnikoff NP,Dodge PW,Dren AT,Kyncl J,Somani P

更新日期：1976-04-01 00:00:00

abstract：:A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar b...

journal_title：Journal of medicinal chemistry

authors： Nair AC,Jayatilleke P,Wang X,Miertus S,Welsh WJ

更新日期：2002-02-14 00:00:00

abstract：:A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 re...

journal_title：Journal of medicinal chemistry

authors： Melnick M,Reich SH,Lewis KK,Mitchell LJ Jr,Nguyen D,Trippe AJ,Dawson H,Davies JF 2nd,Appelt K,Wu BW,Musick L,Gehlhaar DK,Webber S,Shetty B,Kosa M,Kahil D,Andrada D

更新日期：1996-07-05 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：:Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, an...

journal_title：Journal of medicinal chemistry

authors： Chianelli D,Rucker PV,Roland J,Tully DC,Nelson J,Liu X,Bursulaya B,Hernandez ED,Wu J,Prashad M,Schlama T,Liu Y,Chu A,Schmeits J,Huang DJ,Hill R,Bao D,Zoll J,Kim Y,Groessl T,McNamara P,Liu B,Richmond W,Sancho

更新日期：2020-04-23 00:00:00

abstract：:Continuing structure-activity studies on the anticonvulsant activity of analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective index (TD50/ED50) of > 4.5 are reported. An in-depth analysis of this moiety was studied employing the Topliss...

journal_title：Journal of medicinal chemistry

authors： Farrar VA,Ciechanowicz-Rutkowska M,Grochowski J,Serda P,Pilati T,Filippini G,Hinko CN,el-Assadi A,Moore JA,Edafiogho IO

更新日期：1993-11-12 00:00:00

abstract：:PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in wate...

journal_title：Journal of medicinal chemistry

authors： Saavedra JE,Srinivasan A,Buzard GS,Davies KM,Waterhouse DJ,Inami K,Wilde TC,Citro ML,Cuellar M,Deschamps JR,Parrish D,Shami PJ,Findlay VJ,Townsend DM,Tew KD,Singh S,Jia L,Ji X,Keefer LK

更新日期：2006-02-09 00:00:00

abstract：:Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Ex...

journal_title：Journal of medicinal chemistry

authors： Penning TD,Djuric SW,Miyashiro JM,Yu S,Snyder JP,Spangler D,Anglin CP,Fretland DJ,Kachur JF,Keith RH

更新日期：1995-03-17 00:00:00

abstract：:We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered t...

journal_title：Journal of medicinal chemistry

authors： Terasaka T,Okumura H,Tsuji K,Kato T,Nakanishi I,Kinoshita T,Kato Y,Kuno M,Seki N,Naoe Y,Inoue T,Tanaka K,Nakamura K

更新日期：2004-05-20 00:00:00

abstract：:A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques curr...

journal_title：Journal of medicinal chemistry

authors： Pearlman DA,Charifson PS

更新日期：2001-02-15 00:00:00

abstract：:Little is known of the conformation of peptide hormones as they interact with their receptors for a number of reasons: peptide hormones are notoriously flexible in solution, their receptors are particularly complex, and there is strong evidence that receptor-ligand interaction leading to activation is a dynamic proces...

journal_title：Journal of medicinal chemistry

authors： Koerber SC,Rizo J,Struthers RS,Rivier JE

更新日期：2000-03-09 00:00:00

abstract：:The constitution of chlorpromazine has been studied in the context of its phototoxicity. Electron transfer from the side chain to the aromatic nucleus of the drug contributes to its instability to light. Even without the side chain, however, chlorophenothiazines appear to be very photolabile, so that it is unlikely th...

journal_title：Journal of medicinal chemistry

authors： Bunce NJ,Kumar Y,Ravanal L

更新日期：1979-02-01 00:00:00

abstract：:A series of substituted benzenedisulfonamide carbonic anhydrase inhibitors is described and their anticonvulsant activities are listed. One compound, 4-(4-methoxypiperidinosulfonyl)-2-chlorobenzenesulfonamide (19, UK-12130), was found to have anticonvulsant activity in animals at a dose level that gave only a minimal ...

journal_title：Journal of medicinal chemistry

authors： Cross PE,Gadsby B

更新日期：1978-09-01 00:00:00

abstract：:Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerati...

journal_title：Journal of medicinal chemistry

authors： Huang H,Li H,Martásek P,Roman LJ,Poulos TL,Silverman RB

更新日期：2013-04-11 00:00:00

abstract：:Appropriately protected nucleoside 5'-O-(2-thio-1,3,2-dithiaphospholanes) react with inorganic pyrophosphate in the presence of a strong base catalyst (DBU) to give nucleoside 5'-O-(1,1-dithiotriphosphates) 1a-g. The latter compounds, including an AZT analogue, show modest antivirial activity against HIV-1 and HIV-2 r...

journal_title：Journal of medicinal chemistry

authors： Okruszek A,Olesiak M,Balzarini J

更新日期：1994-10-28 00:00:00

abstract：:Coumarins constitute a general and totally new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), binding at the entrance of the active site cavity. We report here that the coumarin-binding site in CAs may interact with diverse compounds, such as the antiepileptic drug lacosamide, which inhibi...

journal_title：Journal of medicinal chemistry

authors： Temperini C,Innocenti A,Scozzafava A,Parkkila S,Supuran CT

更新日期：2010-01-28 00:00:00