Abstract:
:A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA(2): IC(50) = 0.29 microM; P450 arom: IC(50) = 0.50 microM) and its 5, 6-saturated analogue 30 (P450 TxA(2): IC(50) = 0.68 microM; P450 arom: IC(50) = 0.38 microM), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben: IC(50) = 1.1 microM; aminoglutethimide: IC(50) = 18.5 microM). For the determination of the in vivo activity, the influence of selected compounds on serum TxB(2) concentration was examined in rats. Compound 30 (8.5 mg/kg body weight) led to a reduction of the TxB(2) serum level of 78%, 71%, and 51% after 3, 5, and 8 h, respectively (dazoxiben: 60%, 34%, and 36%). Selectivity was studied toward some enzymes of the steroidogenic and eicosanoid pathways. P450 17 was inhibited by selected compounds only at high concentrations. Compound 30 inhibited P450 scc by 13% (25 microM). Compound 31 did not affect cyclooxygenase and lipoxygenase.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Jacobs C,Frotscher M,Dannhardt G,Hartmann RWdoi
10.1021/jm991180ukeywords:
subject
Has Abstractpub_date
2000-05-04 00:00:00pages
1841-51issue
9eissn
0022-2623issn
1520-4804pii
jm991180ujournal_volume
43pub_type
杂志文章abstract::A series of 3-acylbenzamidine (amidino)hydrazones 7a-h, the corresponding (hetero)aromatic congeners 7i-p, and 3,3'-bis-amidino-biaryls 25a-e were synthesized. The hydrazones 7a-p were prepared by conversion of the corresponding acyl nitriles 1a,c-d,i,n-p to the imido esters 3a,c-d,i and the amidines 5a,c-d,h-i, follo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00053a007
更新日期:1993-01-08 00:00:00
abstract::The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400535b
更新日期:2013-06-27 00:00:00
abstract::Ring-constrained adenosine analogues have been designed to act as dual agonists at tissue-protective A(1) and A(3) adenosine receptors (ARs). 9-Ribosides transformed into the ring-constrained (N)-methanocarba-2-chloro-5'-uronamides consistently lost affinity at A(1)/A(2A)ARs and gained at A(3)AR. Among 9-riboside deri...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050726b
更新日期:2005-12-29 00:00:00
abstract::Chlamydia pneumoniae is an intracellular bacterium that responds poorly to antibiotic treatment. Insufficient antibiotic usage leads to chronic infection, which is linked to disease processes of asthma, atherosclerosis, and Alzheimer's disease. The Chlamydia research lacks genetic tools exploited by other antimicrobia...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm1008083
更新日期:2010-11-11 00:00:00
abstract::New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaf...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800113p
更新日期:2008-09-11 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::Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401116k
更新日期:2013-10-10 00:00:00
abstract::Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c00580
更新日期:2020-07-09 00:00:00
abstract::As the number of cases and cancer-related deaths are projected to rise in upcoming years, it is urgent to find ways to prevent or treat cancer. As such, food-derived products have gained attention as potential chemopreventive agents due to their availability, safety, and low cost. Isothiocyanates, the breakdown produc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.8b01698
更新日期:2019-06-13 00:00:00
abstract::A series of novel chiral 7-(1-, 3-, 4-, and 6-methyl-[(1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-substituted naphthyridines has been prepared with the aim of obtaining good in vitro and in vivo antibacterial agents with a decrease of the pseudoallergic type reaction when compared to that observed with 7[(1R,4R)-2,5-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00093a024
更新日期:1992-07-24 00:00:00
abstract::Quantitative structure-activity relationships of the Hansch-type were developed to account for inhibition of thymidine kinases from Herpes simplex viruses types 1 and 2 (HSV1,2) by N2-phenylguanines. Derivatives with meta and/or para substituents on the phenyl ring display a wide range of overlapping, but not identica...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00094a007
更新日期:1992-08-07 00:00:00
abstract::Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR rever...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00530
更新日期:2018-02-08 00:00:00
abstract::4-(Phenylamino)-5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 1 and related compounds known as "diaryltubercidin" analogues are potent inhibitors of adenosine kinase (AK) and are orally active in animal models of pain such as the rat formalin paw model (GP3269 ED50= 6.4 mg/kg). However, the utility...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050394a
更新日期:2005-12-01 00:00:00
abstract::The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400181k
更新日期:2013-05-09 00:00:00
abstract::Reaction of 6-deoxy-2,3,5-tris-O-(p-nitrobenzoyl)-L-talofuranosyl bromide (1) with the trimethylsilyl derivative of hypoxanthine, followed by removal of blocking groups, afforded 9- (6) and 7-(6'-deoxy-alpha-L-talofuranosyl)hypoxanthine (7). A study of the published optical rotations and circular dichroic (CD) spectra...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00364a032
更新日期:1983-10-01 00:00:00
abstract::In our efforts to explore marine cyanobacteria as a source of novel bioactive compounds, we discovered a statine unit-containing linear decadepsipeptide, grassystatin A (1), which we screened against a diverse set of 59 proteases. We describe the structure determination of 1 and two natural analogues, grassystatins B ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9009394
更新日期:2009-09-24 00:00:00
abstract::A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds w...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm1015389
更新日期:2011-03-10 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::A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401899x
更新日期:2014-05-22 00:00:00
abstract::The design, synthesis and pharmacological evaluation of a novel class of Dmt-Tic dipeptide analogues are described. These resulting analogues bearing different C-terminal functionalities were found to bind to the human delta receptor with high affinity. One specific class of dipeptides bearing urea/thiourea functional...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm015532k
更新日期:2001-07-19 00:00:00
abstract::A topological substructural approach to molecular design (TOSS-MODE) has been introduced for the selection and design of anticancer compounds. A quantitative model that discriminates anticancer compounds from the inactive ones in a training series was obtained. This model permits the correct classification of 91.43% o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm991172d
更新日期:2000-05-18 00:00:00
abstract::Kadsurenone, a specific receptor antagonist of platelet-activating factor (PAF), and its analogues were prepared from derivatives of cinnamyl alcohol and (allyloxy)phenol. Racemic kadsurenone, resolvable by a Chiralpak column at low temperatures, has an IC50 value of 2 X 10(-7) M, which is about 50% of the activity of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00384a023
更新日期:1987-01-01 00:00:00
abstract::Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm301824k
更新日期:2013-04-25 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 previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induce...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00039a011
更新日期:1994-06-24 00:00:00
abstract::A critical early event in the inflammatory cascade is the induced expression of cell adhesion molecules on the lumenal surface of vascular endothelial cells. These adhesion molecules include E-selectin, ICAM-1, and VCAM-1, which serve to recruit circulating leukocytes to the site of the inflammation. These adhesive in...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000452m
更新日期:2001-03-15 00:00:00
abstract::The accessible surface, described by Lee and Richards (the L&R surface: J. Mol. Biol. 1971, 55, 379), has remarkably useful properties for displaying ligand-protein interactions. The surface is placed one van der Waals radius plus one probe radius away from the protein atoms. The ligands are displayed in skeletal form...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00088a002
更新日期:1992-05-15 00:00:00
abstract::Tyrosine kinases often play pivotal roles in the pathogenesis of cancer and are good candidates for therapeutic intervention and targeted molecular imaging. The precursor synthesis, radiosynthesis, and biological characterization of a fluorine-18 analog of dasatinib, a multitargeted kinase inhibitor, are reported. Com...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm070342g
更新日期:2007-11-15 00:00:00
abstract::A series of 4-methyl-3-(arylthio)furoxans were synthesized by oxidation of 1-(arylthio)-2-methylglyoxymes with dinitrogen tetroxide. Reduction with trimethyl phosphite of the furoxan derivatives afforded the corresponding furazans, while oxidation with an equimolar amount of 30% hydrogen peroxide in acetic acid or wit...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00095a028
更新日期:1992-08-21 00:00:00
abstract::Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacoki...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9705014
更新日期:1998-01-29 00:00:00