GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile.


:The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723. GNE-5729 (13), a pyridopyrimidinone-based NMDAR PAM, was identified with both an improved pharmacokinetic profile and increased selectivity against AMPARs. We also include X-ray structure analysis and modeling to propose hypotheses for the activity and selectivity differences.


ACS Med Chem Lett


Villemure E,Volgraf M,Jiang Y,Wu G,Ly CQ,Yuen PW,Lu A,Luo X,Liu M,Zhang S,Lupardus PJ,Wallweber HJ,Liederer BM,Deshmukh G,Plise E,Tay S,Wang TM,Hanson JE,Hackos DH,Scearce-Levie K,Schwarz JB,Sellers BD




Has Abstract


2016-10-31 00:00:00










  • Impact of Stereochemistry on Ligand Binding: X-ray Crystallographic Analysis of an Epoxide-Based HIV Protease Inhibitor.

    abstract::A new pseudopeptide epoxide inhibitor, designed for irreversible binding to HIV protease (HIV-PR), has been synthesized and characterized in solution and in the solid state. However, the crystal structure of the complex obtained by inhibitor-enzyme cocrystallization revealed that a minor isomer, with inverted configur...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Benedetti F,Berti F,Campaner P,Fanfoni L,Demitri N,Olajuyigbe FM,De March M,Geremia S

    更新日期:2014-07-14 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


    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

  • Novel 18F-Labeled 1-Hydroxyanthraquinone Derivatives for Necrotic Myocardium Imaging.

    abstract::Rapid detection and precise evaluation of myocardial viability is necessary to aid in clinical decision making whether to recommend revascularization for patients with myocardial infarction (MI). Three novel 18F-labeled 1-hydroxyanthraquinone derivatives were synthesized, characterized, and evaluated as potential necr...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ji AY,Jin QM,Zhang DJ,Zhu H,Su C,Duan XH,Bian L,Sun ZP,Ni YC,Zhang J,Yang Z,Yin ZQ

    更新日期:2016-12-28 00:00:00

  • 1,2,4-Triazolidine-3-thiones as Narrow Spectrum Antibiotics against Multidrug-Resistant Acinetobacter baumannii.

    abstract::With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Huggins WM,Minrovic BM,Corey BW,Jacobs AC,Melander RJ,Sommer RD,Zurawski DV,Melander C

    更新日期:2016-11-12 00:00:00

  • Synthesis, Biological Evaluation, and Autophagy Mechanism of 12N-Substituted Sophoridinamines as Novel Anticancer Agents.

    abstract::A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N'-end could greatly enhance antiproliferation potency. Among them,...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bi C,Zhang N,Yang P,Ye C,Wang Y,Fan T,Shao R,Deng H,Song D

    更新日期:2017-01-05 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


    authors: Wills TJ,Lipkus AH

    更新日期:2020-09-10 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


    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

  • Homogeneous Assay for Target Engagement Utilizing Bioluminescent Thermal Shift.

    abstract::Protein thermal shift assays (TSAs) provide a means for characterizing target engagement through ligand-induced thermal stabilization. Although these assays are widely utilized for screening libraries and validating hits in drug discovery programs, they can impose encumbering operational requirements, such as the avai...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dart ML,Machleidt T,Jost E,Schwinn MK,Robers MB,Shi C,Kirkland TA,Killoran MP,Wilkinson JM,Hartnett JR,Zimmerman K,Wood KV

    更新日期:2018-04-16 00:00:00

  • Rational Design of Cell-Active Inhibitors of PARP10.

    abstract::Poly-ADP-ribose polymerases (PARPs 1-16) have emerged as major regulators of diverse cellular processes. PARPs can be subclassified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While much is known about the cellular roles of PARPs that catalyze PARylation...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Morgan RK,Kirby IT,Vermehren-Schmaedick A,Rodriguez K,Cohen MS

    更新日期:2018-11-29 00:00:00

  • Discovery of a Novel Selective Dual Peroxisome Proliferator-Activated Receptor α/δ Agonist for the Treatment of Primary Biliary Cirrhosis.

    abstract::A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Jiang Z,Liu X,Yuan Z,He H,Wang J,Zhang X,Gong Z,Hou L,Shen L,Guo F,Zhang J,Wang J,Xu D,Liu Z,Li H,Chen X,Long C,Li J,Chen S

    更新日期:2019-06-24 00:00:00

  • Mitragyna speciosa: Balancing Potential Medical Benefits and Abuse.

    abstract::Mitragyna speciosa, also known as kratom, has the potential meet the need for pain medications that lack the addictiveness and overdose risk of classical opioid analgesics, such as morphine. This need is urgent because opioid addiction and overdose deaths have risen throughout diverse segments of U.S. society. Some op...

    journal_title:ACS medicinal chemistry letters

    pub_type: 社论


    authors: Halpenny GM

    更新日期:2017-08-08 00:00:00

  • Antimalarial Properties of Simplified Kalihinol Analogues.

    abstract::Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, s...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Daub ME,Prudhomme J,Ben Mamoun C,Le Roch KG,Vanderwal CD

    更新日期:2017-02-16 00:00:00

  • Lipidated peptidomimetics with improved antimicrobial activity.

    abstract::We report a series of lipidated α-AApeptides that mimic the structure and function of natural antimicrobial lipopeptides. Several short lipidated α-AApeptides show broad-spectrum activity against a range of clinically related Gram-positive and Gram-negative bacteria as well as fungus. Their antimicrobial activity and ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hu Y,Amin MN,Padhee S,Wang RE,Qiao Q,Bai G,Li Y,Mathew A,Cao C,Cai J

    更新日期:2012-07-12 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


    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

  • Structure-Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors.

    abstract::Representative d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zimmermann SC,Rais R,Alt J,Burzynski C,Slusher BS,Tsukamoto T

    更新日期:2014-10-21 00:00:00

  • SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORγ Inhibitor.

    abstract::A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibit...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hirata K,Kotoku M,Seki N,Maeba T,Maeda K,Hirashima S,Sakai T,Obika S,Hori A,Hase Y,Yamaguchi T,Katsuda Y,Hata T,Miyagawa N,Arita K,Nomura Y,Asahina K,Aratsu Y,Kamada M,Adachi T,Noguchi M,Doi S,Crowe P,Bradle

    更新日期:2015-11-04 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


    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

  • 1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain.

    abstract::The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomai...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Demont EH,Bamborough P,Chung CW,Craggs PD,Fallon D,Gordon LJ,Grandi P,Hobbs CI,Hussain J,Jones EJ,Le Gall A,Michon AM,Mitchell DJ,Prinjha RK,Roberts AD,Sheppard RJ,Watson RJ

    更新日期:2014-09-10 00:00:00

  • Small Molecule Lysyl Oxidase-like 2 (LOXL2) Inhibitors: The Identification of an Inhibitor Selective for LOXL2 over LOX.

    abstract::Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC50 = 126 nM), was shown to be selective for LOXL2 over LOX and ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hutchinson JH,Rowbottom MW,Lonergan D,Darlington J,Prodanovich P,King CD,Evans JF,Bain G

    更新日期:2017-03-01 00:00:00

  • Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides.

    abstract::The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gr...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li Y,Lavey NP,Coker JA,Knobbe JE,Truong DC,Yu H,Lin YS,Nimmo SL,Duerfeldt AS

    更新日期:2017-10-19 00:00:00

  • Discovery of an Orally Efficacious Imidazo[5,1-f][1,2,4]triazine Dual Inhibitor of IGF-1R and IR.

    abstract::This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacologica...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Jin M,Gokhale PC,Cooke A,Foreman K,Buck E,May EW,Feng L,Bittner MA,Kadalbajoo M,Landfair D,Siu KW,Stolz KM,Werner DS,Laufer RS,Li AH,Dong H,Steinig AG,Kleinberg A,Yao Y,Pachter JA,Wild R,Mulvihill MJ

    更新日期:2010-08-30 00:00:00

  • Metabolomics Reveal d-Alanine:d-Alanine Ligase As the Target of d-Cycloserine in Mycobacterium tuberculosis.

    abstract::Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic act...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Prosser GA,de Carvalho LP

    更新日期:2013-12-12 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


    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

  • 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


    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

  • Synthesis and Cardiac Imaging of (18)F-Ligands Selective for β1-Adrenoreceptors.

    abstract::A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood poo...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Radeke HS,Purohit A,Harris TD,Hanson K,Jones R,Hu C,Yalamanchili P,Hayes M,Yu M,Guaraldi M,Kagan M,Azure M,Cdebaca M,Robinson S,Casebier D

    更新日期:2011-07-22 00:00:00

  • Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists.

    abstract::A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profil...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu W,Hussain Z,Zang Y,Sweis RF,Romero FA,Finke PE,Moningka R,Bao J,Plotkin MA,Shang J,Dingley KH,Salituro G,Murphy BA,Howard AD,Ujjainwalla F,Wood HB,Duffy JL

    更新日期:2018-10-05 00:00:00

  • Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation.

    abstract::We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystalli...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Farand J,Kropf JE,Blomgren P,Xu J,Schmitt AC,Newby ZE,Wang T,Murakami E,Barauskas O,Sudhamsu J,Feng JY,Niedziela-Majka A,Schultz BE,Schwartz K,Viatchenko-Karpinski S,Kornyeyev D,Kashishian A,Fan P,Chen X,Lansdon EB

    更新日期:2019-11-19 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


    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

  • Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140.

    abstract::This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Miller CP,Shomali M,Lyttle CR,O'Dea LS,Herendeen H,Gallacher K,Paquin D,Compton DR,Sahoo B,Kerrigan SA,Burge MS,Nickels M,Green JL,Katzenellenbogen JA,Tchesnokov A,Hattersley G

    更新日期:2010-12-02 00:00:00

  • Photodynamic Activities of Porphyrin Derivative-Cyclodextrin Complexes by Photoirradiation.

    abstract::Water-soluble cyclodextrin (CyD) complexed with porphyrin derivatives with different substituents in the meso-positions showed different photodynamic activities toward cancer cells under illumination at wavelengths over 600 nm, the most suitable wavelengths for photodynamic therapy (PDT). In particular, aniline- and p...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ikeda A,Satake S,Mae T,Ueda M,Sugikawa K,Shigeto H,Funabashi H,Kuroda A

    更新日期:2017-04-19 00:00:00