当前位置： SCI文献检索 > ACS Medicinal Chemistry Letters期刊下所有文献 > Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

Abstract：

:Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Hoegenauer K,Soldermann N,Stauffer F,Furet P,Graveleau N,Smith AB,Hebach C,Hollingworth GJ,Lewis I,Gutmann S,Rummel G,Knapp M,Wolf RM,Blanz J,Feifel R,Burkhart C,Zécri F

doi

10.1021/acsmedchemlett.6b00119

subject

Has Abstract

pub_date

2016-06-02 00:00:00

pages

762-7

issue

8

issn

1948-5875

journal_volume

7

pub_type

杂志文章

相关文献

ACS Medicinal Chemistry Letters文献大全
  • Computer-aided Drug Design: Using Numbers to your Advantage.

    abstract：:Computer-aided drug design could benefit from a greater understanding of how errors arise and propagate in biomolecular modeling. With such knowledge, model predictions could be associated with quantitative estimates of their uncertainty. In addition, novel algorithms could be designed to proactively reduce prediction...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml4002634

    authors： Faver JC,Ucisik MN,Yang W,Merz KM Jr

    更新日期：2013-09-12 00:00:00

  • Structural Approach to Assessing the Innovativeness of New Drugs Finds Accelerating Rate of Innovation.

    abstract：:Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structu...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.0c00319

    authors： Wills TJ,Lipkus AH

    更新日期：2020-09-10 00:00:00

  • Discovery of a New Class of Potent MMP Inhibitors by Structure-Based Optimization of the Arylsulfonamide Scaffold.

    abstract：:A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1' aromatic portion and a d-proline residue bearing the zinc-binding group. The ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml300446a

    authors： Mori M,Massaro A,Calderone V,Fragai M,Luchinat C,Mordini A

    更新日期：2013-05-14 00:00:00

  • Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.

    abstract：:General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modificatio...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.9b00400

    authors： Fujimoto J,Kurasawa O,Takagi T,Liu X,Banno H,Kojima T,Asano Y,Nakamura A,Nambu T,Hata A,Ishii T,Sameshima T,Debori Y,Miyamoto M,Klein MG,Tjhen R,Sang BC,Levin I,Lane SW,Snell GP,Li K,Kefala G,Hoffman ID,Ding

    更新日期：2019-09-19 00:00:00

  • From Bacteria to Cancer: A Benzothiazole-Based DNA Gyrase B Inhibitor Redesigned for Hsp90 C-Terminal Inhibition.

    abstract：:Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding and maturation of client proteins that are associated with all ten hallmarks of cancer. Hsp90 N-terminal pan inhibitors have experienced unfavorable results in clinical trials due to induction of the heat shock response (HSR), a...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.0c00100

    authors： Pugh KW,Zhang Z,Wang J,Xu X,Munthali V,Zuo A,Blagg BSJ

    更新日期：2020-06-11 00:00:00

  • Discovery of novel benzoxaborole-based potent antitrypanosomal agents.

    abstract：:We report the discovery of benzoxaborole antitrypanosomal agents and their structure-activity relationships on central linkage groups and different substitution patterns in the sulfur-linked series. The compounds showed in vitro growth inhibition IC50 values as low as 0.02 μg/mL and in vivo efficacy in acute murine in...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml100013s

    authors： Ding D,Zhao Y,Meng Q,Xie D,Nare B,Chen D,Bacchi CJ,Yarlett N,Zhang YK,Hernandez V,Xia Y,Freund Y,Abdulla M,Ang KH,Ratnam J,McKerrow JH,Jacobs RT,Zhou H,Plattner JJ

    更新日期：2010-04-06 00:00:00

  • PROTAC Technology: Opportunities and Challenges.

    abstract：:PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, and Boehringer Ingelheim, etc.), and biotechnology ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.9b00597

    authors： Gao H,Sun X,Rao Y

    更新日期：2020-03-12 00:00:00

  • Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site.

    abstract：:Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml5000405

    authors： Chen F,Liu J,Huang M,Hu M,Su Y,Zhang XK

    更新日期：2014-05-14 00:00:00

  • Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase.

    abstract：:Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-a...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.9b00330

    authors： Hiesinger K,Schott A,Kramer JS,Blöcher R,Witt F,Wittmann SK,Steinhilber D,Pogoryelov D,Gerstmeier J,Werz O,Proschak E

    更新日期：2019-10-30 00:00:00

  • Minibody-indocyanine green based activatable optical imaging probes: the role of short polyethylene glycol linkers.

    abstract：:Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml400533y

    authors： Watanabe R,Sato K,Hanaoka H,Harada T,Nakajima T,Kim I,Paik CH,Wu AM,Choyke PL,Kobayashi H

    更新日期：2014-01-17 00:00:00

  • Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy.

    abstract：:Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in p...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.5b00150

    authors： Tosh DK,Crane S,Chen Z,Paoletta S,Gao ZG,Gizewski E,Auchampach JA,Salvemini D,Jacobson KA

    更新日期：2015-05-20 00:00:00

  • Enhanced Cytotoxicity through Conjugation of a "Clickable" Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide.

    abstract：:Re(I) tricarbonyl polypyridine-based complexes are particularly attractive metal complexes in the field of inorganic chemical biology due to their luminescent properties, ease of conjugation to targeting biomolecules, and the possibility to prepare their "hot" (99m)Tc analogues for radioimaging. In this study, we prep...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml500158w

    authors： Leonidova A,Pierroz V,Adams LA,Barlow N,Ferrari S,Graham B,Gasser G

    更新日期：2014-05-15 00:00:00

  • Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides.

    abstract：:Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification o...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.8b00540

    authors： Hu Z,Banothu J,Beesu M,Gustafson CJ,Brush MJH,Trautman KL,Salyer ACD,Pathakumari B,David SA

    更新日期：2018-12-20 00:00:00

  • Synthesis and in vitro and in vivo pharmacological evaluation of new 4-aminoquinoline-based compounds.

    abstract：:A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitr...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml400311r

    authors： Tukulula M,Njoroge M,Abay ET,Mugumbate GC,Wiesner L,Taylor D,Gibhard L,Norman J,Swart KJ,Gut J,Rosenthal PJ,Barteau S,Streckfuss J,Kameni-Tcheudji J,Chibale K

    更新日期：2013-10-01 00:00:00

  • Design and Catalyzed Activation of Tak-242 Prodrugs for Localized Inhibition of TLR4-Induced Inflammation.

    abstract：:Tak-242 (resatorvid), a Toll-like Receptor 4 (TLR4) inhibitor, has been identified as a potent suppressor of innate inflammation. As a strategy to target Tak-242 to select tissue, four TLR4-inactive prodrugs were synthesized for activation via two different release mechanisms. Two nitrobenzyl Tak-242 prodrugs released...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.9b00518

    authors： Plunk MA,Alaniz A,Olademehin OP,Ellington TL,Shuford KL,Kane RR

    更新日期：2020-01-03 00:00:00

  • Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe.

    abstract：:Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel f...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.8b00380

    authors： Paulson CN,Guan X,Ayoub AM,Chan A,Karim RM,Pomerantz WCK,Schönbrunn E,Georg GI,Hawkinson JE

    更新日期：2018-10-31 00:00:00

  • PAR2 Modulators Derived from GB88.

    abstract：:PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining a...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.6b00306

    authors： Yau MK,Liu L,Suen JY,Lim J,Lohman RJ,Jiang Y,Cotterell AJ,Barry GD,Mak JY,Vesey DA,Reid RC,Fairlie DP

    更新日期：2016-10-10 00:00:00

  • Triazole Appending Agent (TAAG): A New Synthon for Preparing Iodine-Based Molecular Imaging and Radiotherapy Agents.

    abstract：:A new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml300003v

    authors： Darwish A,Blacker M,Janzen N,Rathmann SM,Czorny S,Hillier SM,Joyal JL,Babich JW,Valliant JF

    更新日期：2012-02-18 00:00:00

  • Discovery and Assessment of Atropisomers of (±)-Lesinurad.

    abstract：:(+)- and (-)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant differences in hURAT1 highly expressed HEK293 cell-based inhibition assays, monkey pharma...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.6b00465

    authors： Wang J,Zeng W,Li S,Shen L,Gu Z,Zhang Y,Li J,Chen S,Jia X

    更新日期：2017-02-14 00:00:00

  • Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABAA Receptor.

    abstract：:γ-Aminobutyric acid type A (GABAA) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.0c00340

    authors： Blom AEM,Su JY,Repka LM,Reisman SE,Dougherty DA

    更新日期：2020-09-15 00:00:00

  • Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma.

    abstract：:A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overc...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.8b00145

    authors： Huang X,Brubaker J,Zhou W,Biju PJ,Xiao L,Shao N,Huang Y,Dong L,Liu Z,Bitar R,Buevich A,Jung J,Peterson SL,Butcher JW,Close J,Martinez M,MacCoss RN,Zhang H,Crawford S,McCormick KD,Aslanian R,Nargund R,Correll C

    更新日期：2018-06-23 00:00:00

  • Novel carboline derivatives as potent antifungal lead compounds: design, synthesis, and biological evaluation.

    abstract：:A series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against b...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml400492t

    authors： Wang S,Wang Y,Liu W,Liu N,Zhang Y,Dong G,Liu Y,Li Z,He X,Miao Z,Yao J,Li J,Zhang W,Sheng C

    更新日期：2014-02-13 00:00:00

  • Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189.

    abstract：:Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed m...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.7b00343

    authors： Stepan AF,Tran TP,Helal CJ,Brown MS,Chang C,O'Connor RE,De Vivo M,Doran SD,Fisher EL,Jenkinson S,Karanian D,Kormos BL,Sharma R,Walker GS,Wright AS,Yang EX,Brodney MA,Wager TT,Verhoest PR,Obach RS

    更新日期：2018-01-04 00:00:00

  • Transdermal Bioavailability in Rats of Lidocaine in the Forms of Ionic Liquids, Salts, and Deep Eutectic.

    abstract：:Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was di...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.6b00504

    authors： Berton P,Di Bona KR,Yancey D,Rizvi SAA,Gray M,Gurau G,Shamshina JL,Rasco JF,Rogers RD

    更新日期：2017-04-12 00:00:00

  • Design and Synthesis of 2-Alkylpyrimidine-4,6-diol and 6-Alkylpyridine-2,4-diol as Potent GPR84 Agonists.

    abstract：:A series of alkylpyrimidine-4,6-diol derivatives were designed and synthesized as novel GRP84 agonists based on a high-throughput screening (HTS) hit 1. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. These novel GPR84 agonists will provide valuabl...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.6b00025

    authors： Liu Y,Zhang Q,Chen LH,Yang H,Lu W,Xie X,Nan FJ

    更新日期：2016-03-30 00:00:00

  • Auranofin, Et3PAuCl, and Et3PAuI Are Highly Cytotoxic on Colorectal Cancer Cells: A Chemical and Biological Study.

    abstract：:The solution behavior of auranofin, Et3PAuCl  and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward re...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.7b00162

    authors： Marzo T,Cirri D,Gabbiani C,Gamberi T,Magherini F,Pratesi A,Guerri A,Biver T,Binacchi F,Stefanini M,Arcangeli A,Messori L

    更新日期：2017-09-06 00:00:00

  • Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface.

    abstract：:B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein-protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 tha...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.0c00111

    authors： Teng M,Ficarro SB,Yoon H,Che J,Zhou J,Fischer ES,Marto JA,Zhang T,Gray NS

    更新日期：2020-04-03 00:00:00

  • Diphenylpyrazoles as replication protein a inhibitors.

    abstract：:Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carbox...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml5003629

    authors： Waterson AG,Kennedy JP,Patrone JD,Pelz NF,Feldkamp MD,Frank AO,Vangamudi B,Souza-Fagundes EM,Rossanese OW,Chazin WJ,Fesik SW

    更新日期：2014-11-11 00:00:00

  • Small Molecule that Reverses Dexamethasone Resistance in T-cell Acute Lymphoblastic Leukemia (T-ALL).

    abstract：:Glucocorticoids are one of the most utilized and effective therapies in treating T-cell acute lymphoblastic leukemia. However, patients often develop resistance to glucocorticoids, rendering these therapies ineffective. We screened 9517 compounds, selected for their lead-like properties, chosen from among 3 372 615 co...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml500044g

    authors： Cantley AM,Welsch M,Ambesi-Impiombato A,Sanchez-Martin M,Kim MY,Bauer A,Ferrando A,Stockwell BR

    更新日期：2014-04-25 00:00:00

  • Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists.

    abstract：:The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known pip...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.9b00649

    authors： Nakajima R,Oono H,Sugiyama S,Matsueda Y,Ida T,Kakuda S,Hirata J,Baba A,Makino A,Matsuyama R,White RD,Wurz RΡ,Shin Y,Min X,Guzman-Perez A,Wang Z,Symons A,Singh SK,Mothe SR,Belyakov S,Chakrabarti A,Shuto S

    更新日期：2020-02-27 00:00:00