Abstract：
:Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Peterson K,Kumar R,Stenström O,Verma P,Verma PR,Håkansson M,Kahl-Knutsson B,Zetterberg F,Leffler H,Akke M,Logan DT,Nilsson UJdoi
10.1021/acs.jmedchem.7b01626subject
Has Abstractpub_date
2018-02-08 00:00:00pages
1164-1175issue
3eissn
0022-2623issn
1520-4804journal_volume
61pub_type
杂志文章abstract：:Several optically active N-(indol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. IC50 values were measured and revealed that the D form of the amino acid moiety of the compounds was more potent than both the L form and racemic form,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00132a004
更新日期：1989-12-01 00:00:00
abstract：:In the course of studies on tranquilizers, new non-benzodiazepine-like compounds were synthesized. These are 1-(3,4,5-trimethoxyphenoxy)-3-[4-(2-methoxyphenyl)piperazinyl]prop an-2-ol (INN: enciprazine) and derivatives thereof which were screened pharmacologically in order to evaluate their central nervous system acti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00173a012
更新日期：1990-11-01 00:00:00
abstract：:A number of 3-bromo-, 3-nitro-, and 3-ethoxycarbonyl-5,7-dialkylpyrazolo[1,5-a]pyrimidines were synthesized and screened as in vitro cAMP phosphodiesterase inhibitors. The condensation of 3-aminopyrazole with symmetrical beta-diketones (acetylacetone, heptane-3,5-dione, etc.) afforded symmetrical dialkylpyrazolo[1,5-a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00239a004
更新日期：1975-05-01 00:00:00
abstract：:Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains the major obstacle for successful treatment of cancer. Inhibition of Pgp transport is important for higher efficacy of anticancer drugs. Lipophilic cationogenic amines with at least one tertiary N atom, such as verapamil, are classical PgP-blocking ag...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm011010t
更新日期：2002-11-21 00:00:00
abstract：:The photolabile (diazomethyl)carbonyl function was introduced into the 8-position of 2-(N,N-di-n-propyl-amino)-1,2,3,4-tetrahydronaphthalene in three ways, resulting in the ether 8-[[(diazomethyl)carbonyl]methoxy]-2-(N,N-di-n-propylamino)-1,2,3,4- tetrahydronaphthalene (2), the ester 8-(diazoacetoxy)-2-(N,N-di-n-propy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00165a011
更新日期：1990-03-01 00:00:00
abstract：:Bridging chemical and biological space is the key to drug discovery and development. Typically, cheminformatics methods operate under the assumption that similar chemicals have similar biological activity. Ideally then, one could predict a drug's biological function(s) given only its chemical structure by similarity s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060902w
更新日期：2006-11-16 00:00:00
abstract：:3-Aminopyrrolidines bearing acyl substituents on either nitrogen and N-acylated 1,4-diazabicyclo[3.2.1]octanes are potent microfilaricides in the Litomosoides carinii gerbil test system but have no effect on adult worms. The high activity of the pyrrolidine derivatives establishes that diethylcarbamazine (DEC) like an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00220a021
更新日期：1977-10-01 00:00:00
abstract：:A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on the cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200893p
更新日期：2011-11-24 00:00:00
abstract：:Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2013248
更新日期：2012-03-08 00:00:00
abstract：:A series of 9-(hydroxyalkenyl)purines (adenines and 3-deazaadenines), which are analogues of neplanocin A, were synthesized. The analogues were tested as inhibitors of bovine liver and murine L929 cell S-adenosyhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as inhibitors of vaccinia virus replication in murine L929 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00117a011
更新日期：1988-09-01 00:00:00
abstract：:The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the A...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00148a024
更新日期：1985-10-01 00:00:00
abstract：:Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Alth...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00389a011
更新日期：1987-06-01 00:00:00
abstract：:Treatment of a protected 9-(5, 6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine derivative with silver nitrate and N-iodosuccinimide (NIS) and deprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Halogenation of 3-O-benzoyl-5,6-dideoxy-1, 2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-halo acetyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980163m
更新日期：1998-09-24 00:00:00
abstract：:Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01473
更新日期：2021-01-14 00:00:00
abstract：:Lead-like drugs, or drugs below molecular weight 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.8b00407
更新日期：2018-12-13 00:00:00
abstract：:A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives, substituted at the 7-position with functionalized side chains, was synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) as well as ADP- and collagen-induced platelet aggregation, in vitro. Structural modificati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00092a019
更新日期：1992-07-10 00:00:00
abstract：:The polyhalogenated benzimidazole nucleosides 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB) were synthesized in our laboratory and established as potent and selective inhibitors of human cytomegalovirus (HCMV) with a novel mode of action. In an effort to study the behav...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990290y
更新日期：2000-06-15 00:00:00
abstract：:A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (alpha-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-1-(2-naphthalenyl)ethanone), are undergoing clini...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00159a004
更新日期：1986-09-01 00:00:00
abstract：:2,9beta-Dimethyl-2'-hydroxy-6,7-benzomorphan (18) has been synthesized from m-methoxyphenylacetone (6a) or m-methoxyphenylacetonitrile (1) via bromo-alpha-tetralone (10). Isomeric bromo-alpha-tetralone 9, instead of undergoing cyclization to a 6,7-benzomorphan, gave aromatization product 12. The structures and stereoc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00242a005
更新日期：1975-08-01 00:00:00
abstract：:We have synthesized a library of thiosemicarbazones and screened them against three parasitic cysteine proteases, cruzain, falcipain-2, and rhodesain, and against the respective parasite sources of these three proteases, Trypanosoma cruzi, Plasmodium falciparum, and Trypanosoma brucei. The screens identified compounds...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030549j
更新日期：2004-06-03 00:00:00
abstract：:Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-y...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm040855c
更新日期：2005-01-27 00:00:00
abstract：:A series of 1-[[[5-(substituted phenyl)-2-oxazolyl]methylene]amino]- 2,4-imidazolidinediones (6a-t) was synthesized, and the compounds were evaluated for direct skeletal muscle inhibition in the pithed rat gastrocnemius muscle preparation. The correctness of structural assignment of the new series was verified by alte...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00385a006
更新日期：1987-02-01 00:00:00
abstract：:A potent new class of inhibitors of phenylalanyl-tRNA synthetase from Escherichia coli B is described. N-Benzyl-2-phenylethylamine is a competitive inhibitor with respect to L-phenylalanine and appears to possess the structural features required for near-optimal binding. Hydrophobic substituents at the ortho position ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00233a002
更新日期：1976-11-01 00:00:00
abstract：:With the aim of increasing therapeutic indexes of novel cyclic depsinonapeptide pseudomycins, we synthesized and evaluated a series of mono-, di-, and trioxodioxolenylmethyl carbamate prodrugs (2 and 4) of pseudomycin B 1 and pseudomycin C' 3. It is rather encouraging to note that several members of the newly synthesi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000425w
更新日期：2001-08-02 00:00:00
abstract：:From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0342414
更新日期：2004-03-25 00:00:00
abstract：:Dicarba analogues of the cyclic opioid peptides H-Tyr-c[d-Cys-Gly-Phe-d(or l)-Cys]NH2 were synthesized on solid phase by substituting allylglycines for the cysteines and cyclization by ring-closing metathesis between the side chains of the allylglycine residues. Mixtures of cis and trans isomers of the resulting olefi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061294n
更新日期：2007-03-22 00:00:00
abstract：:Reaction of nitric oxide (NO) with L-proline in methanolic sodium methoxide yields a diazeniumdiolate product, C5H7N3O4Na2.CH3OH (PROLI/NO), that can be stabilized in basic solution but that dissociates to proline (1 mol) and NO (2 mol) with a half-life of only 1.8 s at pH 7.4 and 37 degrees C. This kinetic behavior h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960616s
更新日期：1996-10-25 00:00:00
abstract：:Using a combination of in silico and experimental approaches, we present evidence that the G-quadruplex (G4) motif (an alternative higher-order DNA conformation) has regulatory potential. Genome-wide analyses of 99980 human, chimpanzee, mouse, and rat promoters showed enrichment of sequence with potential to adopt G4 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800448a
更新日期：2008-09-25 00:00:00
abstract：:A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM were measured in at least one of two different mammalian ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050499d
更新日期：2005-08-11 00:00:00
abstract：:A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01731
更新日期：2018-02-22 00:00:00
