Abstract：
:Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(circulation) > t1/2(hydrolysis). When PEG derivatives of molecular weight approximately 40 kDa were employed with paclitaxel, ca. 4% by weight of paclitaxel was carried by the water soluble prodrug form, and equivalent in vivo toxicity and increased life expectancy in the P388-treated mouse was observed. An effective method for prescreening prodrugs was found to be the acute murine lethality, which reflects the equivalency of the solubilized transport form and the native drug.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Greenwald RB,Gilbert CW,Pendri A,Conover CD,Xia J,Martinez Adoi
10.1021/jm950475esubject
Has Abstractpub_date
1996-01-19 00:00:00pages
424-31issue
2eissn
0022-2623issn
1520-4804pii
jm950475ejournal_volume
39pub_type
杂志文章abstract：:A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library wa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0509851
更新日期：2006-02-09 00:00:00
abstract：:Several derivatives of erythro-beta-hydroxy-DL-aspartic acid (1) were prepared as a potential inhibitors of L-asparagine synthetase (ASase) from rat Novikoff hepatoma. Benzylation of 1 gave the dibenzyl ester 2 which upon coupling with carbobenzoxyglycine afforded the blocked dipeptide 3. Deblocking of 3 gave glycl-er...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00238a006
更新日期：1975-04-01 00:00:00
abstract：:4,4-Ditritio-(-)-nicotine (5) of high specific activity (4.7 Ci/mmol) has been synthesized from (-)-nicotine via the readily prepared 4,4-dibromocotinine (3). Scatchard analysis of the binding of 5 to the crude mitochondrial fraction of whole rat brain revealed a Ka of 4.7 X 10(6) M-1 and 13 fmol of binding sites/mg o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00182a028
更新日期：1980-08-01 00:00:00
abstract：:A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H 3 receptor inverse agonists. 2-Methyl-3-(4-[[3-(1-pyrrolidinyl)propyl]oxy]phenyl)-5-(trifluoromethyl)-4(3 H)-quinazolinone ( 1) was identified as a promising derivative for further evaluation following optimization of key paramet...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8003834
更新日期：2008-08-14 00:00:00
abstract：:The conformation of the sodium salt of mycophenolic acid (MPA), a potent inhibitor of inosine monophosphate dehydrogenase (IMPD), derived from 1D DIFNOE and 2D ROESY experiments in water and molecular dynamics (MD) is described. The hexenoic acid side chain conformation consistent with the NMR data was similar to that...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950600m
更新日期：1996-03-15 00:00:00
abstract：:The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01180
更新日期：2017-01-26 00:00:00
abstract：:Low permeability across the outer membrane is a major reason why most antibiotics are ineffective against Gram-negative bacteria. Agents that permeabilize the outer membrane are typically toxic at their effective concentrations. Here, we report the development of a broad-spectrum homodimeric tobramycin adjuvant that i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00876
更新日期：2019-10-24 00:00:00
abstract：:2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazoles (2, sulfides) exhibit antibacterial properties that are selective for Helicobacter spp., but they also have an inherent susceptibility to metabolic oxidation to furnish 2-[[(2-pyridyl)methyl]sulfinyl]-1H-benzimidazoles (1), which act as proton pump inhibitors (PPIs). We ha...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0208673
更新日期：2002-09-12 00:00:00
abstract：:Most non-thiol CAAX-peptidomimetic farnesyltransferase inhibitors bear nitrogen-containing heterocycles in place of the terminal cysteine which are supposed to coordinate the enzyme-bound zinc. However, it has been shown that those nitrogen-containing heterocycles can be replaced by carbocyclic aromatic moieties which...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010873j
更新日期：2001-09-13 00:00:00
abstract：:The effect of substitution of the pyrrolo- and indolo-N atoms in tetrahydronaltrindole (TNTI), tetrahydrooxymorphindole (TOMI), and 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-4'-phenyl-6,7:2',3'-pyrrolomorphinan (4) is reported. In opioid functional assays 4 were potent deltaopioid receptor (DOR) antagonists while ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm040817t
更新日期：2004-12-16 00:00:00
abstract：:3-O-tert-Butylmorphine (5) was prepared from 6-O-acetylmorphine (3) via alkylation with N,N-dimethylformamide di-tert-butyl acetal, followed by hydrolytic removal of the 3-(dimethylamino)-2-propenoate group. The same process was used to prepare the tert-butyl ether of levorphanol (6), (-)-3-tert-butoxy-N-methylmorphin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00352a037
更新日期：1982-10-01 00:00:00
abstract：:Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990418b
更新日期：1999-12-16 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：: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：:Androgens are well-known to stimulate prostate cancer (PC) growth. Thus, blockade of androgen production in testes and adrenals by CYP17 inhibition is a promising strategy for the treatment of PC. Moreover, many PC patients suffer from glucocorticoid overproduction, and importantly mutated androgen receptors can be st...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100317b
更新日期：2010-08-12 00:00:00
abstract：:In order to investigate the structural requirements for gastroprotective activity in 6-[[1(S)-(3(S),4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy 6-oxo-3(S)-ammoniohexanoate [AI-77-B, 1], a product of Bacillus pumilus AI-77, nine derivatives were prepared and then tested for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00364a007
更新日期：1983-10-01 00:00:00
abstract：:We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [3H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-su...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950304+
更新日期：1996-03-15 00:00:00
abstract：:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01586
更新日期：2017-04-13 00:00:00
abstract：:All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980303s
更新日期：1998-11-19 00:00:00
abstract：:The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.8b01767
更新日期：2019-01-10 00:00:00
abstract：:A series of novel nitroheterocyclic phosphoramidates has been evaluated for antitumor activity in murine and xenograft tumor models and for toxicity in mice. Significant increases in lifespan and long-term survivors were noted in L1210 leukemia and B16 melanoma models, and both complete and partial tumor regressions w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000359y
更新日期：2001-01-04 00:00:00
abstract：:The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most pote...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501792c
更新日期：2015-02-26 00:00:00
abstract：:Conformationally restricted 2'-spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2'-oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401224y
更新日期：2014-03-13 00:00:00
abstract：:The synthesis and some biological activities of [4-beta-(2-thienyl)-L-alanine]oxytocin are reported. This analogue has been studied in an ongoing exploration of the biological effects of introducing amino acid residues with bulky hydrophobic side chains into the second corner position of the beta turn present in the c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00199a022
更新日期：1978-01-01 00:00:00
abstract：:A series of 2-(1-piperazinyl)pyrazines was synthesized and evaluated for central serotonin-like activity. The most interesting member of the series, 6-chloro-2(1-piperazinyl)pyrazine (3a), had pharmacological properties characteristic of potent central serotoninmimetic activity and only weak peripheral serotoninmimeti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00204a007
更新日期：1978-06-01 00:00:00
abstract：:Three new dimeric analogues of ethidium cation in which the monomeric moieties are linked at the 3' positions by alpha,omega-diethers of varying length and composition have been synthesized. The circular dichroism spectra of all three compounds indicate that they double intercalate, and their effects on the thermal he...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00143a014
更新日期：1981-11-01 00:00:00
abstract：:A variety of nonsteroidal systems can function as ligands for the estrogen receptor (ER), in some cases showing selectivity for one of the two ER subtypes, ER alpha or ER beta. We have prepared a series of heterocycle-based (furans, thiophenes, and pyrroles) ligands for the estrogen receptor and assessed their behavio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010211u
更新日期：2001-11-08 00:00:00
abstract：:Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990252e
更新日期：2000-06-15 00:00:00
abstract：:Starting with 2,6-dichlorophenyl isothiocyanate, 1-(2-aminoethyl)-2-cyano-3-(2,6-dichlorophenyl)guanidine (2) was prepared in three steps. In contrast to the corresponding thiourea 1, this compound was essentially inactive as an antihypertensive agent. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00186a027
更新日期：1980-12-01 00:00:00
abstract：:A number of 7-amino and 7-acylamino substituted 4,4a-dihydro-5H-indeno[1,2-c]pyridazin-3-ones have been synthesized as rigid congeners of hypotensive 6-aryl-5-methyl-4,5-dihydro-3(2H)-pyridazinones and tested as antihypertensive, antithrombotic, antiulcer, and antiinflammatory agents. Unlike the previously described 7...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00161a010
更新日期：1986-11-01 00:00:00
