Abstract：
:The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at the alpha-position were synthesized and tested as reversible inhibitiors against SARS 3CL(pro). Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based "warheads" generated significantly better inhibitors (4a-c, 8a-d) with IC(50) values ranging from 0.60 to 70 microM.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Jain RP,Pettersson HI,Zhang J,Aull KD,Fortin PD,Huitema C,Eltis LD,Parrish JC,James MN,Wishart DS,Vederas JCdoi
10.1021/jm0494873keywords:
subject
Has Abstractpub_date
2004-12-02 00:00:00pages
6113-6issue
25eissn
0022-2623issn
1520-4804journal_volume
47pub_type
杂志文章abstract：:Five new P1-(steroid-21-yl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyro phosphates (ara-CDP-steroids), five 1-beta-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P1-(alkyl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyrophosphat e (ara-CDP-alkyl esters) have been prepared and eva...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a004
更新日期：1985-02-01 00:00:00
abstract：:Peptidyl alpha-keto amides have been synthesized and tested as inhibitors of the cysteine protease calpain. A stereospecific synthesis was devised in which Cbz-dipeptidyl-alpha-hydroxy amides were oxidized with TEMPO/hypochlorite to the corresponding alpha-keto amides. This oxidation was accomplished in good yields an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00044a013
更新日期：1994-09-02 00:00:00
abstract：:A group of compounds, structurally related to metoprolol, in which the aromatic nucleus is formally moved stepwise away from the ethanolamine side chain, has been studied as adrenergic agonists and antagonists. All the compounds were active on the adrenergic receptors and showed similar affinity for the receptor regar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00136a014
更新日期：1981-04-01 00:00:00
abstract：:Inhibition of abasic site repair in the cell seems an attractive strategy to potentiate the action of antitumor DNA alkylating drugs. Molecules that bind specifically and strongly to the abasic site are possible candidates to achieve such inhibition. We explored this strategy by preparing molecule 4 that incorporates ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9901428
更新日期：1999-12-16 00:00:00
abstract：:A series of 1-thia analogues of the pyrrolizine bis(carbamate) 9 (NSC-278214), namely 5-aryl-2,3-dihydropyrrolo-[2,1-b]thiazole-6,7-dimethanol 6,7-bis(isopropylcarbamates) (7a-d), were prepared by multistep syntheses from the proline analogue thiazolidine-2-carboxylic acid. The compounds were tested for growth inhibit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00402a030
更新日期：1988-07-01 00:00:00
abstract：:A series of 6,9-disubstituted purines were tested for their ability to bind to the benzodiazepine receptor in rat brain tissue. One of the most active compounds was 9-(3-aminobenzyl)-6-(dimethylamino)-9H-purine (44) with an IC50 = 0.9 microM, which was only 4.5-fold higher than the IC50 for chlordiazepoxide. Substitut...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00125a015
更新日期：1989-05-01 00:00:00
abstract：:Certain L1210-active bis(guanylhydrazones) have structural and biological properties in common with the DNA minor groove binding, antileukemic, bisquaternary ammonium heterocycles. Monitoring of the DNA binding of the bis(guanylhydrazones), by fluorimetric quantitation of drug displacement of DNA-bound ethidium, shows...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00196a016
更新日期：1979-10-01 00:00:00
abstract：:The understanding of the physiological role of the G-protein coupled serotonin 5-HT(7) receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through this receptor. In this report, we describe two compound classes, chromans ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0498102
更新日期：2004-07-29 00:00:00
abstract：:Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00164a045
更新日期：1990-02-01 00:00:00
abstract：:In our search for potent and receptor-selective agonists and antagonists, we report here the results of D-amino acid substitution at each position of the short peptide gamma-melanocyte-stimulating hormone (gamma-MSH). The native gamma-MSH shows weak binding at all three receptors (i.e., the human MC3, MC4, and MC5) an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000211e
更新日期：2000-12-28 00:00:00
abstract：:Cholecystokinin (CCK) has been identified as a pronociceptive endogenous peptide which also possesses antiopioid actions. CCK may be upregulated in conditions of chronic pain or during sustained morphine administration resulting in attenuation of opioid-mediated pain relief. These complex interactions between opioids ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050921q
更新日期：2006-05-18 00:00:00
abstract：:Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient molecular interactions. This can help identify target proteins and map the ligand's interactome. Diazirine probes have even be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.7b01561
更新日期：2018-08-23 00:00:00
abstract：:We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01858
更新日期：2018-02-22 00:00:00
abstract：:Previously, vibsanin B (ViB) was found to preferentially target HSP90β compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90β-NTD, MD, CTD, and full-length HSP90β, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01395
更新日期：2017-11-09 00:00:00
abstract：:Seven 1,2-dihydroxy-1,2-dihydroacronycine and 1,2-dihydroxy-1,2-dihydro-6-demethoxyacronycine esters and diesters were synthesized via osmic oxidation of acronycine or 6-demethoxyacronycine followed by acylation. The 6-demethoxyacronycine derivatives were found to be inactive, whereas in contrast, all of the acronycin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9602975
更新日期：1996-11-22 00:00:00
abstract：:Tumor suppressor protein, p53, is an intracellular protein that is critical within the biochemical cascade that leads to cell death via apoptosis. Recent studies identified the tetrahydrobenzothiazole analogue, pifithrin-alpha (2), as a p53 inhibitor that was effective in protecting neuronal cells against a variety of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020044d
更新日期：2002-11-07 00:00:00
abstract：:The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701467e
更新日期：2008-06-26 00:00:00
abstract：:The construction of bioactive peptides using β-amino acid-containing sequence patterns is a very promising strategy to obtain analogues that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5010896
更新日期：2014-12-11 00:00:00
abstract：:The solid-phase reductive alkylation of the Lys side chain in positions 6 (D) and 8 (L) and position 8 alone of the LH-RH antagonist [N-Ac-D-Nal,D-Ph2,3,D-Arg6,Phe7,D-Ala10]LH-RH was investigated in an attempt to reduce the histamine-releasing activity inherent to most potent antagonists while retaining high antiovula...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00393a038
更新日期：1987-10-01 00:00:00
abstract：:A series of tetramisole derivatives was synthesized and tested for inhibitory activity against alkaline phosphatase which was partially purified from a murine ascitic neoplasm resistant to 6-thiopurines (Sarcoma 180/TG). These agents included derivatives substituted with halogens, CH3, or NO2 groups at either the meta...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00214a021
更新日期：1977-04-01 00:00:00
abstract：:Synthesis of four arabinofuranosyl derivatives of the antitumor agent 3-deazaguanine is described. By the use of 13C and 1H nuclear magnetic resonance spectroscopy, the structures of these nucleosides were established to be alpha and beta pairs of N-7 and N-9 arabinosides of 3-deazaguanine. In contrast to 3-deazaguani...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00194a014
更新日期：1979-08-01 00:00:00
abstract：:Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the deactivation of fatty acid ethanolamides such as the endogenous cannabinoid anandamide, the intestinal satiety factor oleoylethanolamide, and the peripheral analgesic and anti-inflammatory factor palmitoylethanolamide. In ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm021119g
更新日期：2003-06-05 00:00:00
abstract：:A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00703
更新日期：2016-09-08 00:00:00
abstract：:9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione (1) was designed and synthesized as a nonionic inhibitor for the donor binding site of human blood group B galactosyltransferase (GTB). Enzymatic characterization showed 1 to be extremely specific, as the highly homologous human N-acetylgalact...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300642a
更新日期：2013-03-14 00:00:00
abstract：:6-Substituted 6-deoxy-L-galactose (L-fucose) derivatives were synthesized as potential antimetabolites of L-fucose. The cytotoxic effects of these compounds were evaluated on P388 leukemia cells in culture. The L-fucose analogues which showed the most potent growth inhibition were the sulfonyl ester, bromo, and iodo d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00194a017
更新日期：1979-08-01 00:00:00
abstract：:Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which afte...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501573b
更新日期：2015-01-22 00:00:00
abstract：:Peptide modification with fatty acids is an effective method to improve peptide performance. We previously investigated the fatty acid modification of R-lycosin-I, a cytotoxic peptide derived from lycosin-I from the venom of the spider Lycosa singoriensis. In this study, we further investigated the position effects of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01126
更新日期：2019-12-26 00:00:00
abstract：:The effect of structural change on the biological activity of a series of imidazothiazoles and thiazolobenzimidazoles is described. It was found that compounds with polar substituents at the 2 or 3 position of the ring system are less acutely toxic while maintaining antiinflammatory activity. Other structural changes,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00137a022
更新日期：1981-05-01 00:00:00
abstract：:Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped ve...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0108754
更新日期：2001-10-25 00:00:00
abstract：:Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considere...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100504d
更新日期：2010-10-28 00:00:00
