当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).

Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).

Abstract：

:Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Moffett K,Konteatis Z,Nguyen D,Shetty R,Ludington J,Fujimoto T,Lee KJ,Chai X,Namboodiri H,Karpusas M,Dorsey B,Guarnieri F,Bukhtiyarova M,Springman E,Michelotti E

doi

10.1016/j.bmcl.2011.09.078

subject

Has Abstract

pub_date

2011-12-01 00:00:00

pages

7155-65

issue

23

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)01322-9

journal_volume

21

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Novel 4-N-substituted aryl pent-2-ene-1,4-dione derivatives of piperazinyloxazolidinones as antibacterials.

    abstract：:A few substituted piperazinylphenyloxazolidinone compounds 6-13 having substitution on the distant nitrogen atom of piperazine ring scaffold have been synthesized and evaluated for their antibacterial activity in Gram-positive bacteria. A few compounds showed superior in vitro antibacterial activity against Staphyloco...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.12.025

    authors： Lohray BB,Lohray VB,Srivastava BK,Gupta S,Solanki M,Pandya P,Kapadnis P

    更新日期：2006-03-15 00:00:00

  • Interactions of curcumin with the PfATP6 model and the implications for its antimalarial mechanism.

    abstract：:Despite curcumin has been proved to possess antimalarial effects, the underlying mechanism remains to be elucidated. In this letter, the active site binding modes of curcumin in PfATP6, an important antimalarial target, were investigated using computational docking. It was revealed that curcumin interacts with PfATP6 ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.03.060

    authors： Ji HF,Shen L

    更新日期：2009-05-01 00:00:00

  • Anthranilic sulfonamide CCK1/CCK2 dual receptor antagonists II: tuning of receptor selectivity and in vivo efficacy.

    abstract：:In the previous article we demonstrated how certain CCK2R-selective anthranilic amides could be structurally modified to afford high-affinity, selective CCK1R activity. We now describe our efforts at modulating and optimizing the CCK1R and CCK2R affinities aimed at producing compounds with good pharmacokinetics proper...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.09.065

    authors： Pippel M,Boyce K,Venkatesan H,Phuong VK,Yan W,Barrett TD,Lagaud G,Li L,Morton MF,Prendergast C,Wu X,Shankley NP,Rabinowitz MH

    更新日期：2009-11-15 00:00:00

  • Design and discovery of new pyrimidine coupled nitrogen aromatic rings as chelating groups of JMJD3 inhibitors.

    abstract：:The histone methylation on lysine residues is one of the most studied post-translational modifications, and its aberrant states have been associated with many human diseases. In 2012, Kruidenier et al. reported GSK-J1 as a selective Jumonji H3K27 demethylase (JMJD3 and UTX) inhibitor. However, there is limited informa...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.01.006

    authors： Hu J,Wang X,Chen L,Huang M,Tang W,Zuo J,Liu YC,Shi Z,Liu R,Shen J,Xiong B

    更新日期：2016-02-01 00:00:00

  • Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.

    abstract：:Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd gen...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.07.046

    authors： Du W,Jewell JP,Lin LS,Colandrea VJ,Xiao JC,Lao J,Shen CP,Bateman TJ,Reddy VB,Ha SN,Shah SK,Fong TM,Hale JJ,Hagmann WK

    更新日期：2009-09-01 00:00:00

  • Marine sponge alkaloids as a source of anti-bacterial adjuvants.

    abstract：:Novel approaches that do not rely upon developing microbicidal compounds are sorely needed to combat multidrug resistant (MDR) bacteria. The potential of marine secondary metabolites to serve as a source of non-traditional anti-bacterial agents is demonstrated by showing that pyrrole-imidazole alkaloids inhibit biofil...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.11.018

    authors： Melander RJ,Liu HB,Stephens MD,Bewley CA,Melander C

    更新日期：2016-12-15 00:00:00

  • Synthesis and chloroquine-enhancing activity of Na-deacetyl-ferrocenoyl-strychnobrasiline.

    abstract：:Several strychnobrasiline derivatives have been synthesized to overcome the lack of in vivo reversal activity of the parent compound. In the present study, N(a)-deacetyl-ferrocenoyl-strychnobrasiline was synthesized by condensing N(a)-deacetyl-strychnobrasiline with ferrocenic acid previously treated with oxalyl chlor...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.11.067

    authors： Razafimahefa D,Pélinski L,Martin MT,Ramanitrahasimbola D,Rasoanaivo P,Brocard J

    更新日期：2005-02-15 00:00:00

  • Synthesis and antiproliferative activity of benzocyclobutacarbazol derivatives. A new class of potential antitumor agents.

    abstract：:Several benzocyclobutacarbazol derivatives were synthesized and evaluated for their potential cytotoxic properties. A number of these compounds exhibited significant antiproliferative activity with concomitant interaction with the cell cycle and represent a new class of potential anticancer agents. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(00)00532-1

    authors： Graf-Christophe S,Kuehm-Caubère C,Renard P,Pfeiffer B,Pierré A,Léonce S,Caubère P

    更新日期：2000-12-04 00:00:00

  • The discovery of potent, selective, and orally bioavailable PDE9 inhibitors as potential hypoglycemic agents.

    abstract：:Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.03.024

    authors： Deninno MP,Andrews M,Bell AS,Chen Y,Eller-Zarbo C,Eshelby N,Etienne JB,Moore DE,Palmer MJ,Visser MS,Yu LJ,Zavadoski WJ,Michael Gibbs E

    更新日期：2009-05-01 00:00:00

  • 1,8-Naphthalimide-Cu(ІІ) ensemble based turn-on fluorescent probe for the detection of thiols in organic aqueous media.

    abstract：:A 1,8-naphthalimide-Cu(II) ensemble was rationally designed and synthesized as a new turn-on fluorescent probe utilizing the 'chemosensing ensemble' method for detections of thiols (Cys, Hcy and GSH) with high selectivity over other α-amino acids at pH 7.4 in organic aqueous media (EtOH/HEPES, v/v=9:1). The recognitio...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.03.004

    authors： Shi YG,Yao JH,Duan YL,Mi QL,Chen JH,Xu QQ,Gou GZ,Zhou Y,Zhang JF

    更新日期：2013-05-01 00:00:00

  • Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer.

    abstract：:High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.11.068

    authors： Guo C,Kephart S,Ornelas M,Gonzalez J,Linton A,Pairish M,Nagata A,Greasley S,Elleraas J,Hosea N,Engebretsen J,Fanjul AN

    更新日期：2012-01-15 00:00:00

  • Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with a topically acting antiglaucoma sulfonamide.

    abstract：:The X-ray crystal structure for the adduct of human carbonic anhydrase (hCA) II with a topically acting antiglaucoma sulfonamide (the 2-N,N-diethylaminoethylamide of 5-(4-carboxybenzenesulfonamido-1,3,4-thiadiazole-2-sulfonamide), has been resolved at a resolution of 1.6A. This compound is a very potent inhibitor of t...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.01.096

    authors： Abbate F,Casini A,Scozzafava A,Supuran CT

    更新日期：2004-05-03 00:00:00

  • Novel and highly potent histamine H3 receptor ligands. Part 2: exploring the cyclohexylamine-based series.

    abstract：:Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.06.102

    authors： Labeeuw O,Levoin N,Poupardin-Olivier O,Calmels T,Ligneau X,Berrebi-Bertrand I,Robert P,Lecomte JM,Schwartz JC,Capet M

    更新日期：2011-09-15 00:00:00

  • Novel highly potent mu-opioid receptor antagonist based on endomorphin-2 structure.

    abstract：:The mu-opioid agonists endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2)) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2)) exhibit an extremely high selectivity for the mu-opioid receptor and thus represent a potential framework for modification into mu-antagonists. Here we report on the synthesis and biological evaluation of novel [d-2-...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.01.009

    authors： Fichna J,do-Rego JC,Janecki T,Staniszewska R,Poels J,Broeck JV,Costentin J,Schiller PW,Janecka A

    更新日期：2008-02-15 00:00:00

  • Synthesis, antimycobacterial and antibacterial activity of l-[(1R,2S)-2-fluorocyclopropyl]naphthyridone derivatives containing an oxime-functionalized pyrrolidine moiety.

    abstract：:A series of novel 1-[(1R,2S)-2-fluorocyclopropyl]naphthyridone derivatives 21-24 containing an oxime-functionalized pyrrolidine moiety were designed, synthesized and evaluated for their biological activity. Our results reveal that compounds 21a, 21e and 21j show considerable activity against MTB H37Rv ATCC 27294 (MICs...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.10.027

    authors： Huang J,Liu H,Liu M,Zhang R,Li L,Wang B,Wang M,Wang C,Lu Y

    更新日期：2015-11-15 00:00:00

  • Rapid cleavage of cyclic tertiary amides of Kemp's triacid: effects of ring structure.

    abstract：:The piperidyl and prolyl amides of Kemp's triacid (7 and 8, respectively) have been prepared and their rates of intramolecular acylolysis measured as a function of pD. The piperidyl derivative 7 reacts approximately four-times faster (e.g., t(1/2)=3 min at 20 degrees C and pD7.7) than the previously reported pyrrolidy...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.06.024

    authors： Dougan ML,Chin JL,Solt K,Hansen DE

    更新日期：2004-08-16 00:00:00

  • Eicosapentaenoic-acid-derived isoprostanes: synthesis and discovery of two major isoprostanes.

    abstract：:The stereospecific synthesis of two all-syn-EPA-derived isoprostanes (iPs), 5-epi-8,12-iso-iPF(3alpha)-VI 17 and 8,12-iso-iPF(3alpha)-VI 18, has been accomplished. These two synthetic probes have been used to discover and identify their presence in human urine. The eventual quantitative measurement of these two iPs ma...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.09.008

    authors： Chang CT,Patel P,Kang N,Lawson JA,Song WL,Powell WS,FitzGerald GA,Rokach J

    更新日期：2008-10-15 00:00:00

  • Using hydroxymethylphenoxy derivates with the SPOT technology to generate peptides with authentic C-termini.

    abstract：:The SPOT technology can fulfill most requirements for highly parallel, multiple peptide synthesis of soluble peptides within the upper microgram range. Here, we report on an improved method using hydroxymethylphenoxyacetic acid (HMPA) for 19 amino acids and 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB) for ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.05.116

    authors： Ay B,Landgraf K,Streitz M,Fuhrmann S,Volkmer R,Boisguerin P

    更新日期：2008-07-15 00:00:00

  • Highly increased cellular accumulation of vincristine, a useful hydrophobic antitumor-drug, in multidrug-resistant solid cancer cells induced by a simply reduced taxinine.

    abstract：:Regio- and/or chemo-selective reductions of taxinine (1a), a taxane diterpenoid readily obtainable from the needles of a Japanese yew (Taxus cuspidata), at the 5-O-cinnamoyl and 4-exo-methylene moieties have been accomplished by the catalytic hydrogenation over Pd/C or Rh/C to obtain 5-O-phenylpropionylated taxinine A...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00620-4

    authors： Sako M,Suzuki H,Yamamoto N,Hirota K

    更新日期：1999-12-20 00:00:00

  • [(13)C3,(15)N1]-labeled isodesmosine: A potential internal standard for LC-MS/MS analysis of desmosines in elastin degradation.

    abstract：:Isodesmosine and desmosine are crosslinking amino acids that are present only in elastin. They are useful biomarkers for the degradation of elastin, which occurs during the progression of chronic obstructive pulmonary disease (COPD) and related diseases. This Letter describes the synthesis of [(13)C3,(15)N1]-labeled i...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.03.084

    authors： Tanigawa T,Komatsu A,Usuki T

    更新日期：2015-01-01 00:00:00

  • Synthesis and cytotoxic activity evaluation of 2,3-thiazolidin-4-one derivatives on human breast cancer cell lines.

    abstract：:It is well known that resveratrol (RSV) displayed cancer-preventing and anticancer properties but its clinical application is limited because of a low bioavailability and a rapid clearance from the circulation. Aim of this work was to synthesize pharmacologically active resveratrol analogs with an enhanced structural ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.06.051

    authors： Sala M,Chimento A,Saturnino C,Gomez-Monterrey IM,Musella S,Bertamino A,Milite C,Sinicropi MS,Caruso A,Sirianni R,Tortorella P,Novellino E,Campiglia P,Pezzi V

    更新日期：2013-09-01 00:00:00

  • Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism.

    abstract：:A series of 5-HT(6) ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.03.110

    authors： Harris RN 3rd,Stabler RS,Repke DB,Kress JM,Walker KA,Martin RS,Brothers JM,Ilnicka M,Lee SW,Mirzadegan T

    更新日期：2010-06-01 00:00:00

  • A novel series of potent and selective IKK2 inhibitors.

    abstract：:A novel series of aminopyrimidine IKK2 inhibitors have been developed which show excellent in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The relative potency and selectivity of these compounds has been rationalized using QSAR and structure-based modelling. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.10.047

    authors： Bingham AH,Davenport RJ,Gowers L,Knight RL,Lowe C,Owen DA,Parry DM,Pitt WR

    更新日期：2004-01-19 00:00:00

  • A selective inhibitor of the UFM1-activating enzyme, UBA5.

    abstract：:Protein conjugation with ubiquitin and ubiquitin-like small molecules, such as UFM1, is important for promoting cancer cell survival and proliferation. Herein, the development of the first selective micromolar inhibitor of the UBA5 E1 enzyme that initiates UFM1 protein conjugation is described. This organometallic inh...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.10.015

    authors： da Silva SR,Paiva SL,Bancerz M,Geletu M,Lewis AM,Chen J,Cai Y,Lukkarila JL,Li H,Gunning PT

    更新日期：2016-09-15 00:00:00

  • Synthesis and Vasorelaxant Evaluation of Novel 7-Methoxyl-2,3-disubstituted-quinoxaline Derivatives.

    abstract：:An array of novel 7-methoxyl-2,3-disubstituted quinoxaline derivatives was designed, synthesized and their potential antihypertensive activities were examined, in an attempt to discover potent small molecules with vasorelaxant effects. The vasoactivities of these compounds on vascular tone, as well as underlying mecha...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2021.127785

    authors： Zheng CB,Gao WC,Pang PP,Ma X,Peng LC,Yang L,Li X

    更新日期：2021-01-11 00:00:00

  • The mechanism of the irreversible inhibition of estrone sulfatase (ES) through the consideration of a range of methane- and amino-sulfonate-based compounds.

    abstract：:We report the results of our study into a series of simple phenyl and alkyl sulfamates and alkyl methanesulfonates as potential inhibitors of the enzyme estrone sulfatase (ES). The results of the study show that the substituted phenyl sulfamates are good irreversible inhibitors; the alkyl sulfamate compounds were foun...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)00137-3

    authors： Ahmed S,James K,Owen CP,Patel CK,Sampson L

    更新日期：2002-05-06 00:00:00

  • Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma.

    abstract：:A number of compounds bearing a quaternary ammonium moiety were found to be antagonists with nanomolar binding affinity for the chemokine receptor-2. The structure-activity relationships in the series are described herein along with some detailed characterization of the interesting compounds. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.01.115

    authors： Lagu B,Gerchak C,Pan M,Hou C,Singer M,Malaviya R,Matheis M,Olini G,Cavender D,Wachter M

    更新日期：2007-08-01 00:00:00

  • Austalides V and W, new meroterpenoids from the fungus Aspergillus ustus and their antitumor activities.

    abstract：:Two new austalide meroterpenoids, named austalides V and W (1 and 2), were isolated from the fungus Aspergillus ustus VKM F-4692. Their structures were elucidated by extensive spectroscopic analysis and by comparison with related known compounds. The main structural feature of both compounds is a tetrahydrofuranyl rin...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2019.126708

    authors： Antipova TV,Zaitsev KV,Oprunenko YF,Ya Zherebker A,Rystsov GK,Zemskova MY,Zhelifonova VP,Ivanushkina NE,Kozlovsky AG

    更新日期：2019-11-15 00:00:00

  • Design and syntheses of melanocortin subtype-4 receptor agonists: evolution of the pyridazinone archetype.

    abstract：:The discovery and optimization of a new class of non-peptidyl, pyridazinone derived melanocortin subtype-4 receptor agonists is disclosed. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.09.026

    authors： Ujjainwalla F,Warner D,Walsh TF,Wyvratt MJ,Zhou C,Yang L,Kalyani RN,MacNeil T,Van der Ploeg LH,Rosenblum CI,Tang R,Vongs A,Weinberg DH,Goulet MT

    更新日期：2003-12-15 00:00:00

  • Synthesis of glycosyl phosphoramidates: novel isosteric analogues of glycosyl phosphates.

    abstract：:Several newer isosteric analogues of glycosyl phosphates, namely of glycosyl phosphoramidates, were synthesized in good yields using Staudinger reaction of their corresponding azides with trimethyl phosphite followed by de-O-acetylation. The structure and conformation of the fully protected analogue synthesized, namel...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00469-3

    authors： Kannan T,Vinodhkumar S,Varghese B,Loganathan D

    更新日期：2001-09-17 00:00:00