Abstract：
:We here report the synthesis of compounds structurally related to the high-affinity dopamine D(3) receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (1). All compounds were specifically designed as potential PET radioligands for brain D(3) receptors visualization, having lipophilicity within a range for high brain uptake and weak nonspecific binding (2 < ClogP < 3.5) and bearing a methoxy substituent for easy access to labeling with the positron emitter isotope (11)C. N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4-morpholinyl)benzamide (22), N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(1H-imidazol-1-yl)benzamide (23), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-5-(2-furanyl)-1H-pyrazole-3-carboxamide (24) displayed good D(3) receptor affinities (K(i) values 38.0, 22.6, and 21.3 nM, respectively) and were selective over D(2) receptor. Moreover, compounds 22-24 were able to permeate the Caco-2 cell monolayer, differently from compound 1. Although the goal to identify potential PET radioligands with subnanomolar affinities for D(3) receptor was not achieved, the proposed strategy could be a starting point for future developments.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Leopoldo M,Lacivita E,De Giorgio P,Colabufo NA,Niso M,Berardi F,Perrone Rdoi
10.1021/jm050734skeywords:
subject
Has Abstractpub_date
2006-01-12 00:00:00pages
358-65issue
1eissn
0022-2623issn
1520-4804journal_volume
49pub_type
杂志文章abstract：:A series of cis- and trans-dihydroxycotahydrobenzo[f]quinoline congeners of dopamine has been prepared, in which the N substitutent is H, ethyl, or n-propyl. The trans isomers include the dopamine moiety held rigidly in an antiperiplanar diposition which is believed to be necessary for certian central and peripheral d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00190a002
更新日期：1979-04-01 00:00:00
abstract：:We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximatel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061224g
更新日期：2007-02-22 00:00:00
abstract：:A series of 2,3-diaminopropionanilides was synthesized by acylation of mono- and disubstituted aniline derivatives with 2,3-dibromopropionyl chloride and subsequent amination with the appropriate secondary amines. The target compounds were evaluated in mice for antiarrhythmic efficacy against chloroform-induced tachyc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00141a008
更新日期：1981-09-01 00:00:00
abstract：:Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked function of the structure of the starting ma...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020208q
更新日期：2002-10-10 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：:A series of conjugated hyaluronic acid particles (HAP), composed of a hydrophobic anticancer drug core and hydrophilic cyclodextrin/hyaluronic acid shell, were prepared through self-assembling and characterized by (1)H NMR titration, electron microscopy, zeta potential, and dynamic light-scattering experiments. The na...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4014168
更新日期：2013-12-12 00:00:00
abstract：:We previously have reported four possible binding conformation of dynorphin A (Dyn A) for the central kappa opioid receptors, induced by the address sequence, using a molecular mechanics energy minimization approach. The lowest energy conformation was found to exhibit an alpha-helical conformation in the cyclized addr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950369c
更新日期：1996-03-01 00:00:00
abstract：:Oxadiazoles, like the benzoyl group in a series of imidazo[1,2-a]pyrimidines, have been found to be metabolically stable alternatives to ester groups in benzodiazepine-receptor ligands. This change has lead to a number of compounds which bind to the receptors and which exhibit potent agonist activity in a food-motivat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00111a021
更新日期：1991-07-01 00:00:00
abstract：:High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent tha...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9800090
更新日期：1998-06-18 00:00:00
abstract：:A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human histamine H4 receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX. A total of 255 selected compounds were ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm7014777
更新日期：2008-06-12 00:00:00
abstract：:The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00285
更新日期：2017-08-10 00:00:00
abstract：:In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401992e
更新日期：2014-04-24 00:00:00
abstract：:Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)met...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970705k
更新日期：1998-02-12 00:00:00
abstract：:Fifteen 7-substituted 4-hydroxyquinoline-3-carboxylic acids have been designed to minimize covariance between the physicochemical substituent parameters: pi, MR, and sigmap. The molecules have been synthesized and evaluated for their ability to inhibit the respiration of Ehrlich ascites cells as a whole cell model and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00218a003
更新日期：1977-08-01 00:00:00
abstract：:Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100387d
更新日期：2010-11-11 00:00:00
abstract：:Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered cli...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.5b00326
更新日期：2015-12-24 00:00:00
abstract：:We recently introduced sulfated pentagalloylglucopyranoside (SPGG) as an allosteric inhibitor of factor XIa (FXIa) (Al-Horani et al., J. Med Chem. 2013, 56, 867-878). To better understand the SPGG-FXIa interaction, we utilized eight SPGG variants and a range of biochemical techniques. The results reveal that SPGG's su...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500311e
更新日期：2014-06-12 00:00:00
abstract：:Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301879g
更新日期：2013-05-09 00:00:00
abstract：:The synthesis of cis and trans isomers of N,N-N-trimethyl-2-phenoxycyclohexylammonium bromide, cis-N,N,-N-trimethyl-2(2',6'-xylyloxy)cyclohexylammonium bromide, and N,N-dimethyl-3-phenoxypiperidinium bromide is described. Their structures and conformations were determined by NMR and uv absorption spectroscopy, the min...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00227a022
更新日期：1976-05-01 00:00:00
abstract：:Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00004a008
更新日期：1995-02-17 00:00:00
abstract：:Synthesis and biological activity of 17-esters of 6-dehydro-16-methylene-17 alpha-hydroxyprogesterone are presented. A systematic study of the influence of the alteration of halogen at 6 and the acyl group at 17 on the progestational and antiandrogenic activities of the resulting structures is described. A convenien...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00277a006
更新日期：1972-07-01 00:00:00
abstract：:Structural genomics will yield an immense number of protein three-dimensional structures in the near future. Automated theoretical methodologies are needed to exploit this information and are likely to play a pivotal role in drug discovery. Here, we present a fully automated, efficient docking methodology that does no...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020830i
更新日期：2002-10-10 00:00:00
abstract：:N-(R)- and N-(S)-lactylsphingosine and their corresponding dihydrosphingosine derivatives were synthesized. The antileukemic activities of these compounds were measured by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in human leukemia HL-60 cells. N-(R)- and N-(S)-Lactylsphingosine disp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030125p
更新日期：2003-07-31 00:00:00
abstract：:Drug-resistant bacterial infections and lack of available antibacterial agents in clinical practice are becoming serious risks to public health. We synthesized a new class of haloemodins by modifying a traditional Chinese medicine component, emodin. The novel haloemodin exerts strong inhibitory activity on bacterial t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401685f
更新日期：2014-05-08 00:00:00
abstract：:6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100846r
更新日期：2010-09-23 00:00:00
abstract：:Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00098a002
更新日期：1992-10-02 00:00:00
abstract：:The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050165o
更新日期：2005-09-22 00:00:00
abstract：:A close analogue of the antileukemic agent 5,8-dideaza-N10 propargylfolic acid (2) was synthesized by replacing the propargyl moiety of 2 with a cyanomethyl group. This compound, N10-(cyanomethyl)-5,8-dideazafolic acid (3), was evaluated for its antifolate and antitumor activities in several biological test systems. A...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00358a030
更新日期：1983-04-01 00:00:00
abstract：:Starting with a previously reported linear breast cancer targeting decapeptide WxEAAYQkFL, here we report the synthesis of a novel cyclic peptide analogue cyclic WXEAAYQkFL. The N- to C-terminus amide cyclized peptide with one d-amino acid (k) displayed higher uptake by breast cancer cells, with minimal uptake by the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00163
更新日期：2017-06-22 00:00:00
abstract：:Cancer cell targeting peptides have emerged as a highly efficient approach for selective delivery of chemotherapeutics and diagnostics to different cancer cells. However, the use of α-peptides in pharmaceutical applications is hindered by their enzymatic degradation and low bioavailability. Starting with a 10-mer α-pe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200750x
更新日期：2011-11-10 00:00:00
