Abstract：
:The chemical synthesis and structure-activity relationships of a novel series of 17beta-glucocorticoid butyrolactones possessing either a 16alpha,17alpha-isopropylidene or -butylidene group are described. The sulfur-linked gamma-lactone group was incorporated onto the 17beta-position of the androstane nucleus via Barton ester decarboxylation and trapping the generated 17-radical with butyrolactone disulfides. The glucocorticoid butyrolactones were hydrolyzed in human plasma by the enzyme paraoxonase to the respective hydroxy acids, which were very weak glucocorticoid agonists. The rate of hydrolysis in plasma was very rapid (t1/2 = 4-5 min) in the case of lactones possessing a sulfur atom in the alpha-position of the butyrolactone group, whereas carbon-linked lactones were stable in plasma. 16alpha,17alpha-Butylidenes were more potent glucocorticoid agonists than the corresponding isopropylidene derivatives. Similarly, 1,4-dien-3-ones were more potent than the corresponding 4-en-3-ones. The butyrolactones linked to the steroidal nucleus via the beta-position were more potent glucocorticoid agonists than those linked through the alpha-position of the lactone. The most potent compounds were also shown to be stable in human lung S9 fraction, showed much lower systemic effects than budesonide in the thymus involution test, and possessed topical antiinflammatory activity in the rat ear edema model.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Procopiou PA,Biggadike K,English AF,Farrell RM,Hagger GN,Hancock AP,Haase MV,Irving WR,Sareen M,Snowden MA,Solanke YE,Tralau-Stewart CJ,Walton SE,Wood JAdoi
10.1021/jm001035ckeywords:
subject
Has Abstractpub_date
2001-02-15 00:00:00pages
602-12issue
4eissn
0022-2623issn
1520-4804pii
jm001035cjournal_volume
44pub_type
杂志文章abstract：:Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980642l
更新日期：1999-04-08 00:00:00
abstract：:Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics pr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01605
更新日期：2015-11-12 00:00:00
abstract：:Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclizat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970081i
更新日期：1997-05-23 00:00:00
abstract：:We describe a new method, Compass, for predicting the biological activities of molecules based on the activities and three-dimensional structures of other molecules. The method improves on previous techniques by representing only the surface of molecules, by incorporating a nonlinear statistical method, and by automat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00041a010
更新日期：1994-07-22 00:00:00
abstract：:A novel lysine-based trifunctional chelate 3 was designed, synthesized, and characterized and bears both a chelating moiety (CHX-A' ') for sequestering radiometals (86Y or 111In) and the near-infrared dye Cy5.5 for dual modality PET (or SPECT) and fluorescence imaging, respectively. Successful conjugation of 3 to the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070657w
更新日期：2007-09-20 00:00:00
abstract：:Conjugates of curcumin to two differently sized poly(ethylene glycol) molecules were synthesized in an attempt to overcome the low aqueous solubility of this natural product with cytotoxic activity against some human cancer cell lines. The soluble conjugates exhibited enhanced cytotoxicity as compared to that of the p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm700988f
更新日期：2007-11-29 00:00:00
abstract：:1H-Indolo[3',2':4,5]pyrido[3,2-b]-2-penten-5-olide (6) and 1H,5H-indolo[3',2'-c]-6,7-dihydro-2-pyridone (7), rigid analogues of methyl 4-ethyl-beta-carboline-3-carboxylate (8) and N-methyl-4-ethyl-beta-carboline-3-carboxamide (9), respectively, were synthesized and their in vitro binding affinities to the central type...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00128a023
更新日期：1989-08-01 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：:Membrane transport of nucleosides or nucleobases is mediated by transporters including the equilibrative nucleoside transporters (ENTs), and resistance to antitumor antimetabolite drugs may arise via salvage of exogenous purine or pyrimidine nucleosides or nucleobases by ENT transporters. The therapeutic utility of di...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101493z
更新日期：2011-03-24 00:00:00
abstract：:The binding and solution-phase properties of six inhibitors of FK506 binding protein (FKBP12) were investigated using free energy perturbation techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neurotrophic activity when bound to FKBP12 a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980062o
更新日期：1998-10-08 00:00:00
abstract：:Overexpression of the HER2 receptor is observed in about 30% of breast and ovarian cancers and is often associated with an unfavorable prognosis. We have recently designed an anti-HER2 peptide (AHNP) based on the structure of the CDR-H3 loop of the anti-HER2 rhumAb 4D5 and showed that this peptide can mimic some funct...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000527m
更新日期：2001-08-02 00:00:00
abstract：:Selective inhibition of the isoforms of nitric oxide synthase (NOS) in pathologically elevated synthesis of nitric oxide has great therapeutic potential. We previously reported nitroarginine-containing dipeptide amides and some peptidomimetic analogues as potent and selective inhibitors of neuronal NOS (nNOS). Here we...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030297m
更新日期：2004-01-29 00:00:00
abstract：:N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer's disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated "open channel" state would be u...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01510
更新日期：2015-12-24 00:00:00
abstract：:Plasmodium falciparum lactate dehydrogenase (pfLDH) is a key enzyme for energy generation of malarial parasites and is a potential antimalarial chemotherapeutic target. It is known that the oxamate moiety, a pyruvate analog, alone shows higher inhibition against pfLDH than human LDHs, suggesting that it can be used fo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070336k
更新日期：2007-08-09 00:00:00
abstract：:An application of the neural network to quantitative structure-activity relationship (QSAR) analysis has been studied. The new method was compared with the linear multiregression analysis in various ways. It was found that the neural network can be a potential tool in the routine work of QSAR analysis. The mathematica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm00171a037
更新日期：1990-09-01 00:00:00
abstract：:Every week, articles disclosing new antifungal leads reported as promising starting points for optimization projects are published. In many cases, the mechanism that accounts for their antifungal activity has not been fully elucidated. More significantly, the detrimental impact that could result from certain embedded ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.5b00361
更新日期：2016-01-28 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：:A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500818a
更新日期：2014-08-14 00:00:00
abstract：:Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070644i
更新日期：2007-11-29 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：:Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Le...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9704917
更新日期：1998-03-26 00:00:00
abstract：:N-[2-Hydroxy-5-[2-(methylamino)ethyl]phenyl]methanesulfonamide (SK&F 102652) has been prepared and characterized pharmacologically. It is a potent agonist with an EC50 of 25 nM at alpha 1-adrenoceptors as determined in the isolated perfused rabbit ear artery. On the presynaptic alpha 2-adrenoceptors of the guinea pig ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a017
更新日期：1985-02-01 00:00:00
abstract：:The enantiomers of two isosteric phosphonate analogs of the ether-linked antitumor agent 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OMe) were synthesized and evaluated for their cytotoxicity against various mouse leukemic cell lines in vitro and in vivo. The key step in the synthesis of the alkyloxy a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00029a016
更新日期：1994-02-04 00:00:00
abstract：:A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration proces...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8003784
更新日期：2008-08-28 00:00:00
abstract：:To evaluate nonaromatic catechol bioisosteres, the conformationally restrained enynes 1 and enediynes 2 were synthesized via palladium-catalyzed coupling as the key reaction step. Subsequent receptor binding studies at the dopamine receptor subtypes D(1), D(2 long), D(2 short), D(3), and D(4) showed highly interesting...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991098z
更新日期：2000-02-24 00:00:00
abstract：:A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060521i
更新日期：2006-11-16 00:00:00
abstract：:2beta-Carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and 2beta-carbomethoxy-3beta-(4'-((E)-2-iodoethenyl)phenyl)nortropane (EIENT) (10) were prepared and evaluated in vitro and in vivo for serotonin transporter (SERT) selectivity and specificity. High specific activity [(123)I]ZIENT and [(123)...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0100180
更新日期：2003-03-13 00:00:00
abstract：:In a recent paper (Colotta et al. J. Med. Chem. 2000, 43, 1158-1164) we reported the synthesis and adenosine receptor binding activity of two sets of 2-aryl-1,2,4-triazolo[4,3-a]quinoxalines (A and B) some of which were potent and selective A(1) or A(3) antagonists. In this paper the synthesis of a set of 2-arylpyrazo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000936i
更新日期：2000-08-10 00:00:00
abstract：:Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0609925
更新日期：2006-12-14 00:00:00
abstract：:Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00098
更新日期：2015-03-26 00:00:00
