Abstract：
:This series of reports describe the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. The compounds reported in this paper contain an additional phenyl ring, which has significantly improved the receptor affinity. The effect of changes in the linkage between the two phenyl rings as well as the orientation of the acidic functional group on biological activity are discussed. Many of these compounds have high affinity to the sulfidopeptide leukotriene D4 receptors with Ki values ranging between 2 and 20 nM and are orally active. Compound 27 [RG 12525, 5-[[2-[[4-(2-quinolinylmethoxy)phenoxy]- methyl]phenyl]methyl]-1H-tetrazole] represents the best combination of in vitro and in vivo biological activity in this series and has been selected for further evaluation in clinical studies of asthma.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Huang FC,Galemmo RA Jr,Johnson WH Jr,Poli GB,Morrissette MM,Mencel JJ,Warus JD,Campbell HF,Nuss GW,Carnathan GWdoi
10.1021/jm00166a017subject
Has Abstract,Author List Incompletepub_date
1990-04-01 00:00:00pages
1194-200issue
4eissn
0022-2623issn
1520-4804journal_volume
33pub_type
杂志文章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
pub_type： 杂志文章
doi：10.1021/jm401610c
更新日期：2013-12-27 00:00:00
abstract：:A series of 8-(substituted phenyl) derivatives of theophylline and other 1,3-dialkylxanthines were evaluated for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Theophylline has a similar potency (Ki = 14 microM) at both A1 and A2 receptors. 8-Phenyltheophylline is 25-35-fold ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00382a018
更新日期：1985-04-01 00:00:00
abstract：:The chemokine receptor CXCR4 is a critical regulator of inflammation and immune surveillance, and it is specifically implicated in cancer metastasis and HIV-1 infection. On the basis of the observation that several of the known antagonists remarkably share a C(2) symmetry element, we constructed symmetric dimers with ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2009716
更新日期：2011-11-10 00:00:00
abstract：:Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been reported to be behaviorally inactive or only very weakly active in man and animals; this may be a consequence of its low partition coefficient and resultant inability to penetrate the blood--brain barrier. The acetyl, propionyl, butyryl, isobutyryl, and pivalyl es...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00197a025
更新日期：1979-11-01 00:00:00
abstract：:The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9704311
更新日期：1998-03-12 00:00:00
abstract：:Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00020a020
更新日期：1995-09-29 00:00:00
abstract：:The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0110340
更新日期：2002-06-06 00:00:00
abstract：:A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the mos...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00237a016
更新日期：1975-03-01 00:00:00
abstract：:G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands due to the high conservation of orthosteric binding sit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.6b01601
更新日期：2017-05-25 00:00:00
abstract：:The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00108a030
更新日期：1991-04-01 00:00:00
abstract：:We studied the structure-activity relationships of a series of 2'-fluoro-2',3'-unsaturated D-nucleosides against HIV-1 in human peripheral blood mononuclear (PBM) cells. The target compounds 10-21 and 28-33 were prepared by N-glycosylation of the acetate 4, which was readily prepared from 2,3-O-isopropylidene-D-glycer...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010418n
更新日期：2002-03-14 00:00:00
abstract：:CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01077
更新日期：2018-11-08 00:00:00
abstract：:In the present work, we have designed and synthesized a series of arachidonic acid derivatives of general structure I which have been characterized as highly potent and selective inhibitors of anandamide transporter (IC(50) = 24-0.8 microM, K(i) > 1000-5000 nM for CB(1) and CB(2) cannabinoid receptors and vanilloid VR...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm015545y
更新日期：2001-12-20 00:00:00
abstract：:There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01831
更新日期：2017-05-11 00:00:00
abstract：:Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049614v
更新日期：2005-03-24 00:00:00
abstract：:The superior activity of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea (MeCCNU) against advanced murine Lewis lung carcinoma in comparisons with the cis form and other nitrosoureas prompted the synthesis of a number of MeCCNU analogues, including several cis-trans pairs. The methyl group was replaced b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00212a019
更新日期：1977-02-01 00:00:00
abstract：:Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900697r
更新日期：2009-11-12 00:00:00
abstract：:To improve the biological profile of 20(S)-camptothecin, a novel class of 20-O-linked camptothecin glycoconjugates has been designed for preferential cellular uptake into tumor cells by an active transport mechanism. Such conjugates have been optimized for enhanced solubility, stabilization of the camptothecin lactone...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010893l
更新日期：2001-11-22 00:00:00
abstract：:The stereospecific synthesis of several 4-[(4-carboxyphenyl)oxy]- 3,3-dialkyl-1-[[(1-phenylalkyl)-amino]carbonyl]azetidin-2-on es 3 is described in which the C-3 alkyl groups were varied from methyl to butyl as well as allyl, benzyl and methoxymethyl. The structure-activity relations for these compounds are discussed ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00013a021
更新日期：1995-06-23 00:00:00
abstract：:Hydroxyurea, hydroxyguanidine, and some thiosemicarbazones have been shown to have anticancer and antiviral activities. One of their possible sites of action is the enzyme ribonucleotide reductase (RR). Combination of the structural features of these compounds led to the design and synthesis of the Schiff bases of N-h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00146a022
更新日期：1985-08-01 00:00:00
abstract：:In this paper, a peptide substrate (Pep8) of TSSK1 is identified. Using Pep8 as a substrate, two homogeneous and efficient assays for TSSK1 inhibitors screening have been developed, including luminescent kinase assay and LC-MS-based high-throughput assay. Two classes of compounds were identified that are able to effic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9002846
更新日期：2009-07-23 00:00:00
abstract：:Molecular docking studies of carbohydrate derivatives in protein binding sites are often challenging because of water-mediated interactions and the inherent flexibility of the many terminal hydroxyl groups. Using the recognition process between heat-labile enterotoxin from Escherichia coli and ganglioside GM1 as a par...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980472c
更新日期：1999-05-20 00:00:00
abstract：:A series of peptidyl alpha-ketoacids and alpha-ketoesters was synthesized and studied as mu-calpain inhibitors. Docking studies revealed that the mu-calpain inhibitory activity of the compounds is influenced by hydrogen bonding interactions and the potential for ionic interaction with active site residues as well as p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800182c
更新日期：2008-07-24 00:00:00
abstract：:Four novel steroidal alpha-methylene delta-lactones have been synthesized and shown to be active against human nasopharyngeal carcinoma (KB) cells in culture. The syntheses involved the use of known alpha-methylenation procedures. In addition, the lactone 6 was directly methylenated by reaction with CH2O/KOH or Et2NH/...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00175a019
更新日期：1980-01-01 00:00:00
abstract：:The crystal and molecular structure of metyrapone, a powerful inhibitor of certain cytochromes P-450, is described. Cytochrome P-450 enzymes are involved in metabolic processes, including those activating insecticides, drugs, and carcinogens. Metyrapone inhibits both the adrenal cytochrome P-450 catalyzing 11-beta-hyd...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00363a008
更新日期：1983-09-01 00:00:00
abstract：:The Free-Wilson equations are derived for the case of symmetrical substitution and are applied, in four modifications, to in vitro inhibitory activity of 77 organic disulfides against Histoplasma capsulatum. Substituent constants are listed to aid in the design of new inhibitory agents against this human pathogen (and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00238a004
更新日期：1975-04-01 00:00:00
abstract：:The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. L...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0496133
更新日期：2004-09-23 00:00:00
abstract：:The synthesis of a series of substituted heterocyclic alkoxypropionic acids is described. They were evaluated for antiinflammatory effects in two animal models of chronic inflammation; adjuvant arthritis and type II collagen arthritis in the rat. The desired profile of biological activity was characterized by the redu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00106a044
更新日期：1991-02-01 00:00:00
abstract：:The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives at vascular 5HT1B-like receptors is described. Several important auxiliary binding sites of the 5HT1B-like receptor have been proposed following various modifications to the 2-substituent and especially to the methylene- or...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9605849
更新日期：1997-07-18 00:00:00
abstract：:For a fourth approach of quinoxaline N,N'-dioxides as anti-trypanosomatid agents against T. cruzi and Leishmania, we found extremely active derivatives. The present study allows us to state the correct requirements for obtaining optimal in vitro anti-T. cruzi activity. Derivatives possessing electron-withdrawing subst...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2002469
更新日期：2011-05-26 00:00:00
