当前位置： SCI文献检索 > ACS Medicinal Chemistry Letters期刊下所有文献 > Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.

Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.

Abstract：

:Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Oehlrich D,Peschiulli A,Tresadern G,Van Gool M,Vega JA,De Lucas AI,Alonso de Diego SA,Prokopcova H,Austin N,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Rombouts FJR,Macdonald G,Moechars D,Gijsen HJM,Trabanco AA

doi

10.1021/acsmedchemlett.9b00181

subject

Has Abstract

pub_date

2019-07-02 00:00:00

pages

1159-1165

issue

8

issn

1948-5875

journal_volume

10

pub_type

杂志文章

相关文献

ACS Medicinal Chemistry Letters文献大全
  • Drug Discovery: Collaborations between Contract Research Organizations and the Pharmaceutical Industry.

    abstract：:Collaborations between the pharmaceutical industry and contract research organizations continue to represent an attractive alternative to internal drug discovery within a single organization. This Viewpoint covers many of the business models and strategies that are employed in industry-contract research organization c...

    journal_title：ACS medicinal chemistry letters

    pub_type： 社论

    doi：10.1021/acsmedchemlett.8b00236

    authors： Steadman VA

    更新日期：2018-06-04 00:00:00

  • Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.

    abstract：:The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.5b00403

    authors： Cee VJ,Chavez F Jr,Herberich B,Lanman BA,Pettus LH,Reed AB,Wu B,Wurz RP,Andrews KL,Chen J,Hickman D,Laszlo J 3rd,Lee MR,Guerrero N,Mattson BK,Nguyen Y,Mohr C,Rex K,Sastri CE,Wang P,Wu Q,Wu T,Xu Y,Zhou Y,Wi

    更新日期：2016-02-12 00:00:00

  • Discovery of s-nitrosoglutathione reductase inhibitors: potential agents for the treatment of asthma and other inflammatory diseases.

    abstract：:S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml200045s

    authors： Sun X,Wasley JW,Qiu J,Blonder JP,Stout AM,Green LS,Strong SA,Colagiovanni DB,Richards JP,Mutka SC,Chun L,Rosenthal GJ

    更新日期：2011-03-11 00:00:00

  • Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor.

    abstract：:APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/P...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml500389m

    authors： Buzard DJ,Kim SH,Lopez L,Kawasaki A,Zhu X,Moody J,Thoresen L,Calderon I,Ullman B,Han S,Lehmann J,Gharbaoui T,Sengupta D,Calvano L,Montalban AG,Ma YA,Sage C,Gao Y,Semple G,Edwards J,Barden J,Morgan M,Chen W,U

    更新日期：2014-11-04 00:00:00

  • Synthesis and antibacterial activity of a novel class of 15-membered macrolide antibiotics, "11a-azalides".

    abstract：:An efficient method for the reconstruction of the 9-dihydroerythromycin A macrolactone skeleton has been established. The key steps are oxidative cleavage at the 11,12-position and reconstruction after insertion of an appropriate functionalized amino alcohol. Novel 15-membered macrolides, we named as "11a-azalides", w...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml100252s

    authors： Sugimoto T,Tanikawa T

    更新日期：2010-12-30 00:00:00

  • Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300.

    abstract：:C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.5b00385

    authors： Shrimp JH,Sorum AW,Garlick JM,Guasch L,Nicklaus MC,Meier JL

    更新日期：2015-10-31 00:00:00

  • Synthesis and Antitumor Activity of C-7-Alkynylated and Arylated Pyrrolotriazine C-Ribonucleosides.

    abstract：:A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold w...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.0c00269

    authors： Li Q,Groaz E,Persoons L,Daelemans D,Herdewijn P

    更新日期：2020-07-09 00:00:00

  • Novel modulator of Na(V)1.1 and Na(V)1.2 Na channels in rat neuronal cells.

    abstract：:A novel modulator of sodium ion currents was synthesized in 6 steps from a protected dihydroxypyrrolidine nitrone, via 1,3-dipolar cycloaddition reaction with acrylamide. Sodium ion currents in B50 cells were evaluated in comparison to saxitoxin and tetrodotoxin, and revealed an IC(50) of 15.7 muM. The new compound sh...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml100035t

    authors： Mao H,Fieber LA,Gawley RE

    更新日期：2010-03-31 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

  • GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis.

    abstract：:GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn's and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.9b00636

    authors： Marino S,Finamore C,Biagioli M,Carino A,Marchianò S,Roselli R,Giorgio CD,Bordoni M,Di Leva FS,Novellino E,Cassiano C,Limongelli V,Zampella A,Festa C,Fiorucci S

    更新日期：2020-03-02 00:00:00

  • B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation.

    abstract：:We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray cr...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.8b00407

    authors： Garai S,Raja KS,Papke RL,Deschamps JR,Damaj MI,Thakur GA

    更新日期：2018-10-11 00:00:00

  • Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors.

    abstract：:Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include th...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml400292s

    authors： Haikarainen T,Narwal M,Joensuu P,Lehtiö L

    更新日期：2013-11-20 00:00:00

  • Discovery of 1,4-Naphthoquinones as a New Class of Antiproliferative Agents Targeting GPR55.

    abstract：:A new series of 1,4-naphthoquinones, bearing various cyclic and aliphatic amines on C2, was designed and synthesized to identify antiproliferative agents for triple-negative breast cancer, which represents a clinical challenge without targeted therapies. Among naphthoquinones, 2a and 3a inhibited the proliferation of ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.8b00333

    authors： Badolato M,Carullo G,Caroleo MC,Cione E,Aiello F,Manetti F

    更新日期：2019-02-15 00:00:00

  • Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor.

    abstract：:The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TD...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.8b00369

    authors： Laulumaa S,Hansen KV,Masternak M,Drapier T,Francotte P,Pirotte B,Frydenvang K,Kastrup JS

    更新日期：2018-11-04 00:00:00

  • Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.

    abstract：:The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be n...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml500242y

    authors： Goodwin NC,Cianchetta G,Burgoon HA,Healy J,Mabon R,Strobel ED,Allen J,Wang S,Hamman BD,Rawlins DB

    更新日期：2014-08-07 00:00:00

  • Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry.

    abstract：:An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-c...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.5b00474

    authors： Schmitz J,Li T,Bartz U,Gütschow M

    更新日期：2015-12-28 00:00:00

  • Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator.

    abstract：:The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.7b00546

    authors： Collibee SE,Bergnes G,Muci A,Browne WF 4th,Garard M,Hinken AC,Russell AJ,Suehiro I,Hartman J,Kawas R,Lu PP,Lee KH,Marquez D,Tomlinson M,Xu D,Kennedy A,Hwee D,Schaletzky J,Leung K,Malik FI,Morgans DJ Jr,Morgan BP

    更新日期：2018-02-13 00:00:00

  • EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity.

    abstract：:Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the la...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.5b00037

    authors： Campbell JE,Kuntz KW,Knutson SK,Warholic NM,Keilhack H,Wigle TJ,Raimondi A,Klaus CR,Rioux N,Yokoi A,Kawano S,Minoshima Y,Choi HW,Porter Scott M,Waters NJ,Smith JJ,Chesworth R,Moyer MP,Copeland RA

    更新日期：2015-03-04 00:00:00

  • Optimization of an albumin-binding prodrug of Doxorubicin that is cleaved by prostate-specific antigen.

    abstract：:We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represe...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml100060m

    authors： Elsadek B,Graeser R,Warnecke A,Unger C,Saleem T,El-Melegy N,Madkor H,Kratz F

    更新日期：2010-05-26 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

  • Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs).

    abstract：:Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we repor...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.9b00609

    authors： Tutone M,Pibiri I,Perriera R,Campofelice A,Culletta G,Melfi R,Pace A,Almerico AM,Lentini L

    更新日期：2020-02-18 00:00:00

  • Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR.

    abstract：:Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.6b00005

    authors： Heffron TP,Ndubaku CO,Salphati L,Alicke B,Cheong J,Drobnick J,Edgar K,Gould SE,Lee LB,Lesnick JD,Lewis C,Nonomiya J,Pang J,Plise EG,Sideris S,Wallin J,Wang L,Zhang X,Olivero AG

    更新日期：2016-02-16 00:00:00

  • Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome.

    abstract：:This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inh...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.5b00401

    authors： Wilson DL,Meininger I,Strater Z,Steiner S,Tomlin F,Wu J,Jamali H,Krappmann D,Götz MG

    更新日期：2016-01-15 00:00:00

  • De novo prediction of p-glycoprotein-mediated efflux liability for druglike compounds.

    abstract：:P-glycoprotein (Pgp) is capable of recognizing and transporting a wide range of chemically diverse compounds in vivo. Overcoming Pgp-mediated efflux can represent a significant challenge when penetration into the central nervous system is required or within the context of developing anticancer therapies. While numerou...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml300314h

    authors： Gunaydin H,Weiss MM,Sun Y

    更新日期：2012-11-06 00:00:00

  • Seeking (and Finding) Biased Ligands of the Kappa Opioid Receptor.

    abstract：:The discovery and characterization of two classes of kappa opioid receptor agonists that are biased for G protein over βarrestin signaling are described. ...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.7b00224

    authors： Bohn LM,Aubé J

    更新日期：2017-07-05 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

  • N-Methylated sst2 Selective Somatostatin Cyclic Peptide Analogue as a Potent Candidate for Treating Neurogenic Inflammation.

    abstract：:A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml200032v

    authors： Chatterjee J,Laufer B,Beck JG,Helyes Z,Pintér E,Szolcsányi J,Horvath A,Mandl J,Reubi JC,Kéri G,Kessler H

    更新日期：2011-04-04 00:00:00

  • Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics.

    abstract：:The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a p...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml3000066

    authors： Tang H,Walsh SP,Yan Y,de Jesus RK,Shahripour A,Teumelsan N,Zhu Y,Ha S,Owens KA,Thomas-Fowlkes BS,Felix JP,Liu J,Kohler M,Priest BT,Bailey T,Brochu R,Alonso-Galicia M,Kaczorowski GJ,Roy S,Yang L,Mills SG,Garcia M

    更新日期：2012-03-28 00:00:00

  • Maturing from embryonic to adult policy on stem cell therapeutics.

    abstract：:The National Institutes of Health (NIH) closure of the agency's Center for Regenerative Medicine (CRM), which focused on therapeutic development of induced pluripotent stem cells (iPS), was caused by the lack of progress in practical development of the iPSs for use in human therapies. As the NIH evaluates priorities i...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/ml500396z

    authors： Maguire G

    更新日期：2014-10-08 00:00:00

  • Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability.

    abstract：:Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation...

    journal_title：ACS medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1021/acsmedchemlett.5b00070

    authors： Pettersson M,Johnson DS,Humphrey JM,Butler TW,Am Ende CW,Fish BA,Green ME,Kauffman GW,Mullins PB,O'Donnell CJ,Stepan AF,Stiff CM,Subramanyam C,Tran TP,Vetelino BC,Yang E,Xie L,Bales KR,Pustilnik LR,Steyn SJ,Wood K

    更新日期：2015-04-03 00:00:00