Abstract：
:To study the influence of substitution of CN for C identical to CH in the anti-herpes virus nucleoside 5-(propynyloxy)-2'-deoxyuridine (1), 5-[(cyanomethylene)oxy]-2'-deoxyuridine (2) was prepared. When the potassium salt of 5-hydroxy-2'-deoxyuridine was reacted with iodoacetonitrile in dry DMF, the bisalkylated product 3-(cyanomethyl)-5-[(cyanomethylene)oxy]-2'-deoxyuridine (3) was the major product with a lesser amount of 3-(cyanomethyl)-5-hydroxy-2'-deoxyuridine (5) and only a trace amount of the desired product (2). In contrast, when 5-hydroxy-2'-deoxyuridine was alkylated in water in the presence of 1 equiv of KOH, compound 2 was the major product. In cultures of primary rabbit kidney (PRK) cells, compound 2 showed an anti-herpes virus activity that was comparable to that of 1 and ara-A. Compound 2 did not inhibit incorporation of [Me-3H]dThd or [1',2'-3H]dUrd into DNA of PRK cells; however, its anti-herpes virus activity was completely prevented upon the addition of either dThd or dUrd.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Huang GF,Okada M,De Clercq E,Torrence PFdoi
10.1021/jm00136a007subject
Has Abstractpub_date
1981-04-01 00:00:00pages
390-3issue
4eissn
0022-2623issn
1520-4804journal_volume
24pub_type
杂志文章abstract：:Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with lo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060687j
更新日期：2007-01-25 00:00:00
abstract：:On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4012214
更新日期：2013-11-27 00:00:00
abstract：:The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIA...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400732v
更新日期：2013-10-24 00:00:00
abstract：:Recent studies have indicated several therapeutic applications for delta opioid agonists and antagonists. To exploit the therapeutic potential of delta opioids developing a structural basis for the activity of ligands at the delta opioid receptor is essential. The conformationally sampled pharmacophore (CSP) method (B...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0612463
更新日期：2007-04-19 00:00:00
abstract：:A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biologic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980366a
更新日期：1998-10-22 00:00:00
abstract：:N delta-Acyl derivatives of the potent folylpolyglutamate synthetase (FPGS) inhibitor N alpha-(4-amino-4-deoxypteroyl)-L-ornithine (APA-L-Orn) were synthesized from N alpha-(4-amino-4-deoxy-N10-formylpteroyl)-L-ornithine by reaction with an N-(acyloxy)succinimide or acyl anhydride, followed by deformylation with base....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00402a013
更新日期：1988-07-01 00:00:00
abstract：:Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm401937a
更新日期：2014-10-23 00:00:00
abstract：:The synthesis of 19 (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate prodrugs containing sulfonate leaving groups and 7-substituted electron-withdrawing groups is reported. These were designed to undergo hypoxia-selective metabolism to form potent DNA minor groove-alkylating agents. Analogues 17 and 24, con...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201717y
更新日期：2012-03-22 00:00:00
abstract：:A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluor...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00047a009
更新日期：1994-10-14 00:00:00
abstract：:(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple f...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00121a034
更新日期：1989-01-01 00:00:00
abstract：:c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm502018y
更新日期：2015-03-12 00:00:00
abstract：:Reaction of 3'-acetylthymidine with phosphorus oxychloride in trimethyl phosphate yielded the phosphorodichloridate 5, which was subsequently reacted with aziridine, or 2,2-dimethylaziridine to give compounds 6 and 7, respectively. The 2,2-dimethylaziridine derivative 7 was considerably more active than 6 against leuk...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00139a024
更新日期：1981-07-01 00:00:00
abstract：:Water soluble analogues of the lipophilic immunostimulant, octadecyl D-alanyl-L-glutamine, BCH-527, were synthesized and evaluated for the ability to stimulate natural killer (NK) cells. One of these compounds in which the octadecyl chain of BCH-527 was replaced with a shorter chain alcohol, 6-(D-alanyl-L-glutaminylam...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970734v
更新日期：1998-05-21 00:00:00
abstract：:A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED(50) = 3.5 microg, a value about 3-fold higher wi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900458r
更新日期：2009-12-10 00:00:00
abstract：:A molecular model of the alpha(IIb)beta(3) integrin has been developed utilizing (i). the crystal structure of alpha(v)beta(3), (ii). homology model of the alpha(IIb) subdomain, and (iii). the docking of alpha(IIb)beta(3)/alpha(v)beta(3) dual and selective inhibitors into the putative binding sites of alpha(IIb)beta(3...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030146j
更新日期：2003-12-04 00:00:00
abstract：:The ability of molecular docking, using the program Glide and an MM-GBSA postdocking scoring protocol, to correctly rank a number of congeneric kinase inhibitors was assessed. The approach was successful for the cases considered and suggests that this may be useful for the design of inhibitors in the lead optimization...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060522a
更新日期：2006-08-10 00:00:00
abstract：:A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. Th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00024a008
更新日期：1995-11-24 00:00:00
abstract：:2'-Deoxy-2'-isocyano-1-beta-D-arabinofuranosylcytosine (8, NCDAC) has been synthesized as a potential antitumor antimetabolite from a corresponding 2'-azido-2'-deoxy-1-beta-D-arabinofuranosyluracil derivative 2a. Uracil and thymine analogues 6a and 6b of 8 were also prepared. Attempts to synthesize 2'-deoxy-2'-isocyan...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00078a007
更新日期：1993-12-24 00:00:00
abstract：:The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute corona...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800180e
更新日期：2008-06-12 00:00:00
abstract：:The protein kinase MKK7 is linked to neuronal development and the onset of cancer. The field, however, lacks high-quality functional probes that would allow for the dissection of its detailed functions. Against this background, we describe an effective covalent inhibitor of MKK7 based on the pyrazolopyrimidine scaffol...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00102
更新日期：2019-03-14 00:00:00
abstract：:A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]cloni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00375a017
更新日期：1984-09-01 00:00:00
abstract：:A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3K...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00193
更新日期：2020-04-23 00:00:00
abstract：:A series of methylated analogues of 6-hydroxydopamine (6-OHDA) has been synthesized and evaluated as irreversible inhibitors of catechol O-methyltransferase (COMT). These analogues have been prepared in an effort to elucidate the mechanism involved in the inactivation of this enzyme by 6-OHDA. The analogues prepared h...
journal_title：Journal of medicinal chemistry
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doi：10.1021/jm00232a007
更新日期：1976-10-01 00:00:00
abstract：:Several candidate retinoid antagonists were designed on the basis of the ligand superfamily concept and synthesized. Retinoidal activities of these benzimidazole and benzodiazepine derivatives were examined by assay of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. The parent benzim...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00036a017
更新日期：1994-05-13 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：:A series of analogues of the dipeptide sweetener L-aspartyl-L-phenylalanine methyl ester having hydroxy and/or methoxy substitution on the aromatic ring was synthesized and tasted. The introduction of a methoxy group in the para position of the aromatic ring of the peptide sweetener is crucial to the reduction or dest...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00178a013
更新日期：1980-04-01 00:00:00
abstract：:In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) models are important tools in combating late-stage attrition in the drug discovery process. This work shows how ADMET models can be combined to tailor predictions depending on one's needs. We demonstrate how the judicious use of data and c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049254b
更新日期：2005-02-24 00:00:00
abstract：:4-[4-(N-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0201114
更新日期：2002-09-26 00:00:00
abstract：:Molecular docking studies of carbohydrate derivatives in protein binding sites are often challenging because of water-mediated interactions and the inherent flexibility of the many terminal hydroxyl groups. Using the recognition process between heat-labile enterotoxin from Escherichia coli and ganglioside GM1 as a par...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980472c
更新日期：1999-05-20 00:00:00
abstract：:9-acridinyl derivatives of 1,6-hexanediamine, 1,8-octanediamine, bis(3-aminopropyl)amine, N,N'-bis(3-amino-propyl)piperazine, and N-ethyl-1,6-hexanediamine in the form of their hydrochlorides were prepared in high yields and converted into potential hetero bis DNA intercalating diacridines. The corresponding potential...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00364a028
更新日期：1983-10-01 00:00:00
