Abstract:
:Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase as compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Koeberle SC,Fischer S,Schollmeyer D,Schattel V,Grütter C,Rauh D,Laufer SAdoi
10.1021/jm300327hsubject
Has Abstractpub_date
2012-06-28 00:00:00pages
5868-77issue
12eissn
0022-2623issn
1520-4804journal_volume
55pub_type
杂志文章abstract::A structure-activity study was performed to examine the role of position 14 of human alpha-calcitonin gene-related peptide (h-alpha-CGRP) in activating the CGRP receptor. Interestingly, position 14 of h-alpha-CGRP contains a glycyl residue and is part of an alpha-helix spanning residues 8-18. Analogues [Ala14]-h-alpha...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9608164
更新日期:1997-09-12 00:00:00
abstract::Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-y...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm040855c
更新日期:2005-01-27 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::A series of novel, disulfide-constrained human beta-melanocyte stimulating hormone (beta-MSH)-derived peptides were optimized for in vitro melanocortin-4 receptor (MC-4R) binding affinity, agonist efficacy, and selectivity. The most promising of these, analogue 18, was further studied in vivo using chronic rat food in...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0501432
更新日期:2005-05-05 00:00:00
abstract::Screening in mixtures is a common approach for increasing the efficiency of high-throughput screening. Here we investigate how the "compound load" of mixtures influences promiscuous aggregate-based inhibition. We screened 764 molecules individually and in mixtures of 10 at 5 miccroM each, comparing the observed inhibi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060029z
更新日期:2006-04-06 00:00:00
abstract::We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine h...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300208p
更新日期:2012-05-10 00:00:00
abstract::Di-tert-butyl (E)-4,4'-stilbenedicarboxylate and tert-butyl 4-vinylbenzoate were copolymerized with maleic anhydride and tert-butyl 4-maleimidobenzoate, individually and respectively. After conversion into polyanions, these four copolymers exhibited activity against four HIV-1 strains: IIIb, BaL, JR-CSF, and 92UG037. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401913w
更新日期:2014-08-14 00:00:00
abstract::Glycosylation of 2-fluoroadenine with the appropriate protected thioglycoside derivatives, followed by deprotection and anomer separation, produced the alpha- and beta-anomers of 2',5'-dideoxy-2-fluoroadenosine (1), 2',5'-dideoxy-2,5'-difluoroadenosine (2), and 2'-deoxy-2-fluoroadenosine (3). These were examined as P-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0303599
更新日期:2004-02-26 00:00:00
abstract::Two-bivalent ligands (P-X-P) containing the beta-naltrexamine pharmacophore (P) and a connecting oligoethylene glycol spanner (X) were synthesized and evaluated for narcotic antagonistic activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD). The bivalent ligand 2 whose spanner contains three ethylene uni...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00349a016
更新日期:1982-07-01 00:00:00
abstract::We previously reported (J. Med. Chem. 1993, 36, 1188-1193) that changes to the ring size of the piperidine and cyclohexyl rings of the high-affinity and selective dopamine (DA)-uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 2) caused different, and in some cases opposite, changes in affinity for...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00077a011
更新日期:1993-12-10 00:00:00
abstract::Recently, FXIIa was highlighted as an original attractive target for the development of new anticoagulant drugs with low rates of therapy-related hemorrhages. In this work, we describe the development of a new series of 3-carboxamide-coumarins that are the first potent and selective nonpeptidic inhibitors of FXIIa. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8002697
更新日期:2008-06-12 00:00:00
abstract::A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antib...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00375a003
更新日期:1984-09-01 00:00:00
abstract::Various substituted isoquinoline-1-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia. Condensation of 4-bromo-1-methylisoquinoline (4) with ammonium hydroxide, methylamine, ethylamine, and N-acetylethylenediamine gave the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00021a012
更新日期:1995-10-13 00:00:00
abstract::A new series of pyrazolotriazolopyrimidines bearing different substitutions on the phenylcarbamoyl moieties at the N5 position, being highly potent and selective human A(3) adenosine receptor antagonists, is described. The compounds represent an extension and an improvement of our previous work on this class of compou...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0109614
更新日期:2002-02-14 00:00:00
abstract::Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b02022
更新日期:2020-03-26 00:00:00
abstract::Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm4002007
更新日期:2013-04-25 00:00:00
abstract::Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is respons...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400080c
更新日期:2013-06-13 00:00:00
abstract::Inhibition of histone deacetylase (HDAC) results in growth arrest, differentiation, and apoptosis in nearly all tumor cell lines, promoting HDACs as promising targets for antitumor therapy. In our previous study we developed a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDAC inhibit...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm101605z
更新日期:2011-04-28 00:00:00
abstract::Members of a series of basic amide and ester derivatives of 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids were prepared and evaluated for their ability to prevent slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea. The results indicate that the presence of a branched-cha...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00365a016
更新日期:1983-11-01 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::A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this comp...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980077m
更新日期:1998-07-02 00:00:00
abstract::Modulation of sphingosine 1-phosphate (S1P) signaling represents a solid opportunity for multiple sclerosis (MS) treatment. In this issue, a team at Novartis reports on the identification of the first direct S1P lyase (S1PL) inhibitors as new MS agents. One of the most potent inhibitors reported in their work was demo...
journal_title:Journal of medicinal chemistry
pub_type: 评论,杂志文章
doi:10.1021/jm500845y
更新日期:2014-06-26 00:00:00
abstract::Factors influencing dose potency of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogues in L1210 assays have been investigated by multiple regression analysis. The dependent variable was D40, the dose to provide 40% life extension in L1210 tests. Independent variables examined were chromatographic Rm val...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00137a009
更新日期:1981-05-01 00:00:00
abstract::Racemic ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazine-7- carbamate (1a) has shown antitumor activity in a variety of in vivo experiments. The preparation of the R and S isomers gave compounds with significant differences in potency in several biological tests. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00129a012
更新日期:1989-09-01 00:00:00
abstract::A series of twenty alkyl-, halo-, and methoxy-aryl-substituted 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic acids were synthesized. The new compounds, called CSAB, suppressed proliferation of human cervix carcinoma, HeLa cells, in vitro in a concentration range of 0.644 to 29.48 microM/L. Two compounds exhibit ant...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0502889
更新日期:2005-08-25 00:00:00
abstract::Fifteen anthracene-9,10-dione ("anthraquinone") derivatives with (omega-aminoalkyl)carboxamido substituents at the 1-, 2-, 1,4-, or 2, 6-ring positions were tested for bacterial mutagenicity in reverse-mutation assays using Salmonella typhimurium frameshift strains TA1538, TA98, and TA97a, in the presence and absence ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980167r
更新日期:1998-09-10 00:00:00
abstract::We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate exp...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01431
更新日期:2021-01-14 00:00:00
abstract::A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited H...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5001503
更新日期:2014-04-24 00:00:00
abstract::Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was emp...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500463c
更新日期:2014-06-12 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