Abstract：
:We report twelve analogues of [Pmp1,D-Trp2,Arg8]oxytocin, ANTAG (Pmp = beta, beta-pentamethylene-beta-mercaptopropionic acid), which is a potent antagonist (pA2 = 7.77) of the uterotonic effect of oxytocin (OT) in rats, as measured in a uterotonic assay. Nine of the following analogues were designed by replacement of each of the nine residues in ANTAG with an L-tryptophan residue: [Ac-Trp1,D-Trp2,Val6,Arg8]OT, [Pmp1,Trp2,Arg8]OT, [Pmp1,D-Trp2,Trp3,Arg8]OT, [Pmp1,D-Trp2,Trp4,Arg8]OT, [Pmp1,D-Trp2,Trp5,Arg8]OT, [Aaa1,D-Trp2,Trp6,Arg8]OT, [Aaa1,D-Trp2,Val6,Arg8]OT, [Pmp1,D-Trp2,Ica7,Arg8]OT, [Pmp1,D-Trp2,Trp7,Arg8]OT, [Pmp1,D-Trp2,Trp8]OT, [Pmp1,D-Trp2,Arg8,Trp9]OT (11), [Pmp1,D-Trp2,Arg8,Trp(For)9]OT (12). In these analogues Aaa = 1-adamantaneacetic acid, and Ica = indoline-2-carboxylic acid. All linear analogues and analogues featuring Trp substitutions in the ring sequence of ANTAG were OT antagonists of lower potency than the parent peptide. All the analogues featuring Trp substitutions in the tail sequence of ANTAG were OT antagonists of equal or better potency than the parent peptide. Replacement with Ica7 gave analogue 8, equipotent with ANTAG, but replacement with Trp7 gave analogue 9, which shows almost a two-fold increase in potency (pA2 = 8.06). Replacement with Trp9 gave analogue 11 (pA2 = 8.03) which is about 1.8 times more potent than the parent antagonist, although Trp(For)9 had lower potency. Of great interest is that substitution with Trp8 leads to a more potent analogue, 10 (pA2 = 8.22), which, unlike most antidiuretic hormone antagonists, lacks any cationic charge in the molecule. The antidiuretic assay shows antagonists 9-11 to be weak antagonists of [Arg8]vasopressin, the antidiuretic hormone, with pA2 less than or equal to 6.0; hence, they may be interesting leads for future design of more potent and specific OT antagonists.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Flouret G,Brieher W,Majewski T,Mahan K,Wilson L Jrdoi
10.1021/jm00111a025subject
Has Abstractpub_date
1991-07-01 00:00:00pages
2089-94issue
7eissn
0022-2623issn
1520-4804journal_volume
34pub_type
杂志文章abstract：:1 (MTC-220), a conjugate of paclitaxel and a muramyl dipeptide analogue, has been synthesized as a novel agent of dual antitumor growth and metastasis activities. In vitro and in vivo tests show that 1 retains its ability to inhibit tumor growth. It is superior to paclitaxel in its ability to prevent tumor metastasis ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101577z
更新日期：2011-04-28 00:00:00
abstract：:The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline 1, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin1), wh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101144f
更新日期：2010-10-14 00:00:00
abstract：:We previously reported (J. Med. Chem. 1993, 36, 1188-1193) that changes to the ring size of the piperidine and cyclohexyl rings of the high-affinity and selective dopamine (DA)-uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 2) caused different, and in some cases opposite, changes in affinity for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00077a011
更新日期：1993-12-10 00:00:00
abstract：:Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibite...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01190
更新日期：2016-11-23 00:00:00
abstract：:A series of quinone substrates were modeled into the active site of human DT-diaphorase and minimized. Correlation of these models with the substrate specificity k(cat)/K(m) provided insights into the structural requirements of quinone substrates. The W105, F106, and H194 residues can influence the position of the qui...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0104365
更新日期：2002-03-14 00:00:00
abstract：:Dequalinium (4) is a potent and selective blocker of small conductance Ca2+-activated K+ channels, an important but relatively little studied class. The 4-NH2 group of dequalinium has been shown to contribute significantly to blocking potency. In this study, we have investigated further the role of the 4-NH2 group. Re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00018a013
更新日期：1995-09-01 00:00:00
abstract：:The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00081a021
更新日期：1992-02-07 00:00:00
abstract：:A series of 2-aryldopamine analogues were synthesized and evaluated for their effects on D1 and D2 dopamine receptors. The 2-phenyldopamine and 6-phenylbenzazepine analogues exhibited weak binding to both D1 and D2 receptors. The 9-(aminomethyl)fluorenes also exhibited weak D2 binding; however, 2,5,6-trihydroxy-9H-flu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00160a018
更新日期：1986-10-01 00:00:00
abstract：:New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are ca...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400529f
更新日期：2013-06-13 00:00:00
abstract：:In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these com...
journal_title：Journal of medicinal chemistry
pub_type： 信件
doi：10.1021/jm015577l
更新日期：2002-03-28 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
pub_type： 杂志文章
doi：10.1021/jm00058a010
更新日期：1993-03-19 00:00:00
abstract：:Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibito...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01869
更新日期：2018-04-26 00:00:00
abstract：:Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501072b
更新日期：2014-12-26 00:00:00
abstract：:Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGF...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01894
更新日期：2017-04-13 00:00:00
abstract：:The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100977d
更新日期：2010-11-11 00:00:00
abstract：:Gossypol and 17 derivatives were tested as inhibitors of aldose reductase from human placenta. Gossypol and a number of the derivatives were potent inhibitors. The order of inhibitory activity was interpreted in relation to the Kador-Sharpless pharmacophor model for the aldose reductase inhibitor site. The structural ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00115a021
更新日期：1991-11-01 00:00:00
abstract：:Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by inve...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01888
更新日期：2020-09-24 00:00:00
abstract：:The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in dept...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3003697
更新日期：2012-05-10 00:00:00
abstract：:A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00084a014
更新日期：1992-03-20 00:00:00
abstract：:Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7)...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00736
更新日期：2017-12-14 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300233k
更新日期：2012-07-26 00:00:00
abstract：:A 2A adenosine receptor antagonists usually have bi- or tricyclic N aromatic systems with varying substitution patterns to achieve desired receptor affinity and selectivity. Using a pharmacophore model designed by overlap of nonxanthine type of previously known A 2A antagonists, we synthesized a new class of compounds...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701594y
更新日期：2008-08-14 00:00:00
abstract：:A series of tetrazole amide derivatives of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide (1) was prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in vivo. For this series of compounds, o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960170f
更新日期：1996-06-07 00:00:00
abstract：:Two analogues, 6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran and 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran, of the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were synthesized and tested in the two-lever drug discrimination paradigm. In rats trained to discriminate s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00152a022
更新日期：1986-02-01 00:00:00
abstract：:The cyclic AMP phosphodiesterase (cAMP PDE) inhibitor and cardiotonic agent lixazinone (N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro-2- oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide, RS-82856, 1) and its acid and base addition salts were found to be insufficiently soluble in formulations suitable for intravenous adm...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00119a015
更新日期：1988-11-01 00:00:00
abstract：:Conjugation of pleuromutilin is an attractive strategy for the development of novel antibiotics and the fight against multiresistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01328
更新日期：2020-12-24 00:00:00
abstract：:Four highly charged, water soluble platinum-acridine bisintercalating agents have been synthesized. Depending on the cis/trans isomerism of the metal and the nature of the acridine side chains, bisintercalation induces/stabilizes the classical Watson-Crick B-form or a non-B-form. Circular dichroism spectra and chemica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8003569
更新日期：2008-06-12 00:00:00
abstract：:Syntheses of several tripeptide analogues of leupeptin containing C-terminal argininal, lysinal, or ornithinal units are presented. The synthetic analogues were tested as inhibitors of trypsin, plasmin, and kallikrein. (Benzyloxycarbonyl)-L-leucyl-L-leucyl-L-argininal (2a) was significantly less effective as an inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00163a014
更新日期：1990-01-01 00:00:00
abstract：:Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of he...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500531z
更新日期：2014-06-26 00:00:00
abstract：:3,4-Dihydro-2(1H)-quinolones, evolved from 2-carboxy-1,2,3,4,- tetrahydroquinolines and 3-carboxy-4-hydroxy-2(1H)-quinolones, have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA receptor and for AMPA [(RS)-alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid] antag...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00074a021
更新日期：1993-10-29 00:00:00
