Abstract：
:The effect of aromatic nitro compounds on the oxidative metabolism of representative type I (hexobarbital and aminopyrene) and type II (aniline and zoxazolamine) substrates by cytochrome P-450 dependent liver enzymes was studied. Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2-nitronaphthalene) inhibited the oxidation of type II substrates by rabbit liver microsomal enzymes; however, they had no effect on the metabolism of the type I compounds. Inhibition of type II metabolism was characterized graphically as S,I-hyperbolic non-competitive. The influence of aromatic nitro compounds on the interaction of type I and type II substrates with oxidized and reduced cytochrome P-450 was studied by difference spectroscopy. From Lineweaver-Burke plots, nitro compounds were shown to competitively interact with type II compounds for cytochrome p-450 binding sites. Nitro compounds completely prevented the appearance of a type I binding spectrum with either hexobarbital or aminopyrene even when the modifier was present at concentrations less than 10(-8)M. Aromatic nitro compounds appear to therefore inhibit the metabolism of the type II substrates through a mixed mechanism of interaction with the microsomal drug-metabolizing enzymes.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Sternson LA,Gammans REdoi
10.1021/jm00223a034keywords:
subject
Has Abstractpub_date
1976-01-01 00:00:00pages
174-7issue
1eissn
0022-2623issn
1520-4804journal_volume
19pub_type
杂志文章abstract：:Factors influencing dose potency of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogues in L1210 assays have been investigated by multiple regression analysis. The dependent variable was D40, the dose to provide 40% life extension in L1210 tests. Independent variables examined were chromatographic Rm val...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00137a009
更新日期：1981-05-01 00:00:00
abstract：:Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving ch...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01891
更新日期：2018-07-26 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：:The synthesis and in vitro antiplatelet activity significant data of coumarin derivatives 5i-x and quinolin-2(1H)-one derivatives 22a,b, as well as the corresponding structure-activity relationships are described. The recently reported 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin 5f and its potent 7-(2-morp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0611511
更新日期：2007-06-14 00:00:00
abstract：:A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineopla...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000045a
更新日期：2000-07-13 00:00:00
abstract：:The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200808v
更新日期：2011-10-27 00:00:00
abstract：:Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the se...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00099a004
更新日期：1992-10-16 00:00:00
abstract：:Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00585
更新日期：2015-09-10 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：:Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00505
更新日期：2016-07-28 00:00:00
abstract：:Several substance P analogues containing various D-amino acid modifications have been synthesized by the solid-phase procedure, detached from the solid support by ammonolysis, and purified by gel filtration combined with reversed-phase chromatography. Three compounds were fair to very potent competitive antagonists of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00353a008
更新日期：1982-11-01 00:00:00
abstract：:C-terminal fragment analogues of the leech anticoagulant peptide hirudin represent a unique class of thrombin inhibitors that blocks thrombin's cleavage of fibrinogen but does not block the catalytic site of thrombin. In this paper, a series of synthetic peptides were prepared by solid-phase methodology to determine t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00400a020
更新日期：1988-05-01 00:00:00
abstract：:Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compoun...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501285x
更新日期：2015-01-22 00:00:00
abstract：:By use of standard cuprate methodology, a series of 18-cycloalkyl analogues of enisoprost was prepared in an effort to impede omega chain metabolism and prolong duration of gastric antisecretory activity. An initial product of omega chain oxidation, the C-20 hydroxy analogue, was also synthesized for pharmacological c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00125a013
更新日期：1989-05-01 00:00:00
abstract：:Membrane-bound aminopeptidase P (AP-P) participates in the degradation of bradykinin in several vascular beds. We have developed an inhibitor of AP-P called apstatin (1) (N-[(2S, 3R)-3-amino-2-hydroxy-4-phenyl-butanoyl]-L-prolyl-L-prolyl-L-al aninam ide); IC50,human = 2.9 microM. In the rat, apstatin can potentiate th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9805642
更新日期：1999-07-01 00:00:00
abstract：:A series of new amine cyanoborane derivatives were synthesized and exhibited antifungal activity. A long alkyl chain attached to the nitrogen of the amine cyanoboranes and carboxyboranes enhances antifungal activity. An enhanced activity was also obtained upon the halogenation of the amine cyanoboranes as well as in t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060476e
更新日期：2006-08-10 00:00:00
abstract：:Substituted 6-anilinouracils were found to be potent inhibitors of the replication-specific enzyme, DNA polymerase III, from Bacillus subtilis. Inhibition potency was maximized by inclusion of small alkyl groups or halogens in the meta and para positions of the phenyl ring; polar substituents decreased activity consi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00175a007
更新日期：1980-01-01 00:00:00
abstract：:In an attempt to synthesize pentamidine-aplysinopsin hybrid molecule 25, a lead molecule 8 (containing Z-configured aplysinopsin moiety) was identified for antileishmanial activity. Optimization of lead 8 provided 24 (containing E-configured aplysinopsin) possessing 10 times more activity and 401-fold less toxicity th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900564x
更新日期：2009-10-08 00:00:00
abstract：:Both in vitro and in vivo metabolism studies suggested that 5-(2,8-bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) with previously reported antituberculosis activity is rapidly converted to two metabolites 3a and 3b. In order to improve the metabolic stability of this se...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900340a
更新日期：2009-11-26 00:00:00
abstract：:A variety of dicarboxylic acid linkers introduced between the alpha-amino group of Pro(6) and the -amino group of Lys(10) of the cyclic lactam alpha-melanocyte-stimulating hormone (alpha-MSH)-derived Pro(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2 pentapeptide template lead to nanomolar range and selective hMC3...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070461w
更新日期：2008-01-24 00:00:00
abstract：:The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01702
更新日期：2016-02-11 00:00:00
abstract：:Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicoc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00857
更新日期：2015-11-25 00:00:00
abstract：:Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluor...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401764a
更新日期：2014-02-13 00:00:00
abstract：:In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, 1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl-betulinic acid (MSB) analogues were also ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901782m
更新日期：2010-04-22 00:00:00
abstract：:A pharmacophore for the phosphono amino acid antagonists of the NMDA receptor has been developed using computer-based molecular modeling techniques. An important feature of this model is that a single binding site is proposed for the phosphonic acid moiety. All competitive antagonists we have examined incorporating am...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00087a002
更新日期：1992-05-01 00:00:00
abstract：:A series of pyridine-2-carboxaldehyde N-oxide and pyridine-2-carboxaldehyde (thio)phosphoric hydrazones and two cupric chelates was synthesized. The hydrazones, chelates, and combinations of hydrazones and cupric chloride were tested against mice bearing P388 lymphocytic leukemia, Sarcoma 180, or Ehrlich carcinoma asc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00209a011
更新日期：1978-11-01 00:00:00
abstract：:The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9910369
更新日期：1999-08-12 00:00:00
abstract：:The oxazolidinones are a new class of synthetic antibacterials effective against a broad range of pathogenic Gram-positive bacteria, including multi-drug-resistant strains. Linezolid is the first drug from this class to reach the market and has become an important new option for the treatment of serious infections, pa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm058204j
更新日期：2005-07-28 00:00:00
abstract：:Certain L1210-active bis(guanylhydrazones) have structural and biological properties in common with the DNA minor groove binding, antileukemic, bisquaternary ammonium heterocycles. Monitoring of the DNA binding of the bis(guanylhydrazones), by fluorimetric quantitation of drug displacement of DNA-bound ethidium, shows...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00196a016
更新日期：1979-10-01 00:00:00
abstract：:A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocryst...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00439
更新日期：2019-07-11 00:00:00
