Abstract：
:Since the Z isomer of chlorprothixene (1) is far more active than its E counterpart, it was of interest to develop a stereoselective synthesis for this class of compounds. Insertion of a benzenesulfonamido group at the peri position of a chlorprothixene precursor did affect the stereochemistry of side-chain olefin formation, but after hydrolysis attempted removal of the resulting amine led to a Widman-Stoermer cyclization to afford the corresponding tetracyclic pyridazine-containing compound (4). Since this material displayed encouraging activity in neurotransmitter uptake inhibition studies, compounds in which the sulfur bridge was replaced with an ethano bridge similar to that found in imipramine (8) and with sulfur removed (7) were also prepared. These, together with the corresponding peri amino compounds (3, 5, and 6), were tested as neurotransmitter-uptake The two bridged arylamines 3 and 6 displayed potent and selective inhibition of norepinephrine uptake both when tested in vitro and after in vivo administration. The pyridazine-containing compounds exhibited reasonable activity in vitro, but the activity was lost when they were administered in vivo. None of the compounds displayed significant ability to interfere with spiroperidol binding.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Ross BS,Wiley RAdoi
10.1021/jm00145a005subject
Has Abstractpub_date
1985-07-01 00:00:00pages
870-5issue
7eissn
0022-2623issn
1520-4804journal_volume
28pub_type
杂志文章abstract：:(E)-Vinylphosphonate ((E)-VP), a metabolically stable phosphate mimic at the 5'-end of the antisense strand, enhances the in vivo potency of siRNA. Here we describe a straightforward synthetic approach to incorporate a nucleotide carrying a vinylphosphonate (VP) moiety at the 5'-end of oligonucleotides under standard ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01147
更新日期：2018-02-08 00:00:00
abstract：:Gamma9delta2T cells represent the most abundant population of human blood gammadeltaT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus-containing antigens in the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049861z
更新日期：2004-08-26 00:00:00
abstract：:The syntheses and full retinoid receptor characterization of a novel series of retinoic acid receptor alpha (RAR alpha) antagonists, 1-5, are described. These compounds bind with high affinity to RAR alpha but were completely inactive in gene transactivation. They were also potent and effective antagonists of retinoic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9703911
更新日期：1997-08-01 00:00:00
abstract：:Gene therapy based on gene delivery is a promising strategy for the treatment of human disease. Here we present data on structure/biological activity of new biodegradable cholesterol-based cationic lipids with various heterocyclic cationic head groups and linker types. Enhanced accumulation of nucleic acids in the cel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901022t
更新日期：2009-11-12 00:00:00
abstract：:Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct se...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00078
更新日期：2016-05-12 00:00:00
abstract：:Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activitie...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200063s
更新日期：2011-05-26 00:00:00
abstract：:Proteins which bind methylated lysines ("readers" of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200045v
更新日期：2011-04-14 00:00:00
abstract：:Hyperfibrinolytic situations can lead to life-threatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, ε-aminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crys...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01060
更新日期：2020-02-27 00:00:00
abstract：:A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00026a011
更新日期：1995-12-22 00:00:00
abstract：:A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the opt...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401621g
更新日期：2014-03-13 00:00:00
abstract：:A series of alpha,alpha-diaryl-1-piperidinebutanols was evaluated for antiarrhythmic activity in the coronary ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group yielded compounds with the best antiarrhythmic profiles in this series. The length of the methylene ch...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00105a003
更新日期：1991-01-01 00:00:00
abstract：:A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200734j
更新日期：2011-08-25 00:00:00
abstract：:Thirty compounds related to the selective dopamine-autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine have been synthesized and tested for central dopamine-autoreceptor stimulating activity. The 3-(3-hydroxyphenyl)piperidine moiety seems indispensable for high potency and selectivity. Introduction of an add...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00144a021
更新日期：1981-12-01 00:00:00
abstract：:Three [5-t-BuPro(7)]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butylproline for proline in oxytocin, [Mpa(1)]oxytocin, and [dPen(1)]oxytocin. Relative to oxytocin, [5-t-BuPro(7)]oxytocin and [Mpa(1),5-t-BuPro(7)]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990090m
更新日期：2000-04-20 00:00:00
abstract：:The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991129q
更新日期：2000-04-06 00:00:00
abstract：:Inherently conducting polymers (ICPs) are a specific category of synthetic polymers with distinctive electro-optic properties, which involve conjugated chains with alternating single and double bonds. Polyaniline (PANI), as one of the most well-known ICPs, has outstanding potential applications in biomedicine because ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.9b00803
更新日期：2020-01-09 00:00:00
abstract：:Isolated hepatocytes carry out the N-demethylation of dansylamide at near linear rates for up to 8 h. This reaction was measured by following the release of tritium into water on hydroxylation of 3H-labeled methyl groups. The competitive inhibition of dansylamide by dansylated amino acids was studied in this system as...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00233a013
更新日期：1976-11-01 00:00:00
abstract：:Ras proteins regulate signal transduction processes that control cell growth and proliferation. Their disregulation is a common cause of human tumors. Atomic level structural and dynamical information in a membrane environment is crucial for understanding signaling specificity among Ras isoforms and for the design of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061053f
更新日期：2007-02-22 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：:Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Mo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01960
更新日期：2019-03-28 00:00:00
abstract：:Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested agains...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990467o
更新日期：2000-04-20 00:00:00
abstract：:The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC(50) = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure-antid...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2015952
更新日期：2012-04-12 00:00:00
abstract：:Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.9b01701
更新日期：2020-05-28 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：:A series of dihydrobenzopyrans and tetrahydroquinolines was synthesized and pharmacologically tested for their ability to inhibit P-glycoprotein mediated daunomycin efflux in multidrug resistant CCRF-CEM vcr1000 cells. Several compounds exhibit activities in the range of the reference compounds verapamil and propafeno...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980517+
更新日期：1999-06-03 00:00:00
abstract：:Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00159
更新日期：2015-06-11 00:00:00
abstract：:(+)-Deoxoartelinic acid (13), a new hydrolytically stable, water-soluble, and potent non-acetal-type antimalarial drug candidate, was successfully prepared from artemisinic acid by using sulfur ylide and photooxygenative cyclization in seven steps. This compound showed superior in vitro antimalarial activity against t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020244p
更新日期：2002-10-24 00:00:00
abstract：:In previous studies we demonstrated that lipophilic (99m)Tc-labeled LTB4 antagonist 1 (RP517) accumulated in infectious foci in rabbits, but hepatobiliary clearance hampered imaging of abdominal lesions. We now report the use of cysteic acid as a pharmacokinetic modifier to improve the water solubility and renal clear...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050383h
更新日期：2005-10-06 00:00:00
abstract：:Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701478a
更新日期：2008-06-26 00:00:00
abstract：:SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0155502
更新日期：2001-10-11 00:00:00
