Abstract：
:Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Black WC,Brideau C,Chan CC,Charleson S,Chauret N,Claveau D,Ethier D,Gordon R,Greig G,Guay J,Hughes G,Jolicoeur P,Leblanc Y,Nicoll-Griffith D,Ouimet N,Riendeau D,Visco D,Wang Z,Xu L,Prasit Pdoi
10.1021/jm980642lkeywords:
subject
Has Abstractpub_date
1999-04-08 00:00:00pages
1274-81issue
7eissn
0022-2623issn
1520-4804pii
jm980642ljournal_volume
42pub_type
杂志文章abstract：:Developing methods to incorporate protein flexibility into structure-based drug design is an important challenge. Our approach uses multiple protein structures (MPS) to create a receptor-based pharmacophore model of the desired target. We have previously demonstrated the success of the method by applying it to human i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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abstract：:A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900735p
更新日期：2009-12-10 00:00:00
abstract：:Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and poten...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00982
更新日期：2021-01-14 00:00:00
abstract：:Proton magnetic spectra have been recorded for muscarine and two biologically active cyclopentane analogues. In order to observe homonuclear intramolecular nuclear Overhauser effects, the -N+(CH3)3 signal was irradiated and increases in integrated intensities for other key signals in the molecule were observed. The re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00205a028
更新日期：1978-07-01 00:00:00
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
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doi：10.1021/jm800648y
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abstract：:The problem of structure-activity relationships in sulfonamide type compounds is tackled on the ground that both bacteriostatic activities and structural indices must be referred to the specific individual forms assumed by sulfa drugs in the active solutions. The frequency value of the symmetric stretching mode of the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00244a002
更新日期：1975-10-01 00:00:00
abstract：:1H-Indolo[3',2':4,5]pyrido[3,2-b]-2-penten-5-olide (6) and 1H,5H-indolo[3',2'-c]-6,7-dihydro-2-pyridone (7), rigid analogues of methyl 4-ethyl-beta-carboline-3-carboxylate (8) and N-methyl-4-ethyl-beta-carboline-3-carboxamide (9), respectively, were synthesized and their in vitro binding affinities to the central type...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00128a023
更新日期：1989-08-01 00:00:00
abstract：:A novel series of 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues has been prepared to probe the steric and electronic properties of the binding pocket of the MT(2) receptor accommodating the "out-of-plane" substituent of MT(2)-selective antagonists. The acetamide (6b) bearing an usubstituted indoline moiety ...
journal_title：Journal of medicinal chemistry
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doi：10.1021/jm800974d
更新日期：2009-02-12 00:00:00
abstract：:The plant metabolite 3,4,5-tri-O-galloylquinic acid methyl ester (TGAME, compound 6) was synthesized, and its potential effect on calcium oxalate monohydrate (COM) crystal binding to the surface of Madin-Darby canine kidney cells type I (MDCKI) and crystal growth in a Drosophila melanogaster Malpighian tubule (MT) mod...
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doi：10.1021/acs.jmedchem.7b01566
更新日期：2018-02-22 00:00:00
abstract：:Photodynamic therapy uses a combination of light, oxygen, and a photosensitizer to induce the death of malignant cells. To improve the selectivity of a photosensitizer toward cancerous cells that express gonadotropin-releasing hormone (GnRH) receptors, protoporphyrin IX (PpIX) was conjugated to a GnRH agonist, [d-Lys6...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020535y
更新日期：2003-09-11 00:00:00
abstract：:We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030862l
更新日期：2003-09-11 00:00:00
abstract：:We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antid...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00099a018
更新日期：1992-10-16 00:00:00
abstract：:The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00167a018
更新日期：1990-05-01 00:00:00
abstract：:Antimicrobial resistance (AMR) represents a hot topic in drug discovery. Besides the identification of new antibiotics, the use of nonantibiotic molecules to block resistance mechanisms is a powerful alternative. Bacterial efflux pumps exert an early step in AMR development by allowing bacteria to grow at subinhibitor...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00791
更新日期：2018-09-13 00:00:00
abstract：:The dopamine D(3) receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D(3) versus D(2) receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moie...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030836n
更新日期：2003-08-28 00:00:00
abstract：:A systematic investigation of the impact of spermidine analogues both in vitro and in vivo is described. The study characterizes the effects of these analogues on L1210 cell growth, polyamine pools, ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, spermidine/spermine N1-acetyltransferase, the maintenanc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960849j
更新日期：1997-05-09 00:00:00
abstract：:An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00186a020
更新日期：1980-12-01 00:00:00
abstract：:A novel water-soluble paclitaxel prodrug, isotaxel 2, that realizes a higher water-solubility and the formation of paclitaxel through a simple pH-dependent chemical mechanism via the O-N acyl migration was synthesized and showed promising results in water-solubility and kinetics. This prodrug, a 2'-O-benzoyl isoform o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm034112n
更新日期：2003-08-28 00:00:00
abstract：:Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01957
更新日期：2020-03-26 00:00:00
abstract：:A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clog...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2003552
更新日期：2011-07-14 00:00:00
abstract：:The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors mu, kappa, delta), with 14-phenylpropoxym...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030878b
更新日期：2003-09-11 00:00:00
abstract：:Cancer cells generally generate higher amounts of reactive oxygen species than normal cells. On the basis of this difference, prodrugs have been developed (e.g., hydroxyferrocifen), which remain inactive in normal cells, but become activated in cancer cells. In this work we describe novel aminoferrocene-based prodrugs...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2014937
更新日期：2012-01-26 00:00:00
abstract：:The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970004n
更新日期：1997-06-06 00:00:00
abstract：:New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00035a012
更新日期：1994-04-29 00:00:00
abstract：:Nine representatives of the title series of compounds [(ClCH2CH2)2NP(O)(NH2)ON = CRR'] were synthesized as potential anticancer prodrugs, based on the possibility of enzymatic reduction of the N-O bond to release the known cytotoxic agent phosphoramide mustard [1, (ClCH2CH2)2NP(O)(NH2)OH]. The dimethyl derivative (2, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00366a029
更新日期：1983-12-01 00:00:00
abstract：:The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060435i
更新日期：2006-08-10 00:00:00
abstract：:A series of aryl bicyclic analogs of succinimide and glutarimide was prepared and evaluated for CNS depressant activity. The 8a-aryl-3,4,6,7,8,8a-hexahydro-2H-pyrrolo[2,1-beta][1,3]oxazin-6-ones possessed the best overall spectrum of activity relative to the standard agents glutethimide and phenobarbital. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00225a023
更新日期：1976-03-01 00:00:00
abstract：:For disease network intervention, up-regulating enzyme activities is equally as important as down-regulating activities. However, the design of enzyme activators presents a challenging route for drug discovery. Previous studies have suggested that activating 15-lipoxygenase (15-LOX) is a promising strategy to interven...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01011
更新日期：2016-05-12 00:00:00
abstract：:A series of thymidylate synthetase inhibitors was synthesized, some of which were potential irreversible inhibitors. 5-Formyl-2'-deoxyuridine (9) and its dithiolane derivative 11 were prepared by condensation of the bis(trimethylsilyl) derivative of 5-formyluracil dimethyl acetal and the protected chloro sugar followe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00229a010
更新日期：1976-07-01 00:00:00
abstract：:A variety of nitroheterocyclic carbamate prodrugs of phenylenediamine mustard and 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indoline (amino-seco-CBI-TMI), covering a wide range of reduction potential, were prepared and evaluated for use in gene-directed enzyme prodrug ther...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030308b
更新日期：2003-12-04 00:00:00
