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










  • 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


    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

  • Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.

    abstract::Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alky...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Drakopoulos A,Tzitzoglaki C,McGuire K,Hoffmann A,Konstantinidi A,Kolokouris D,Ma C,Freudenberger K,Hutterer J,Gauglitz G,Wang J,Schmidtke M,Busath DD,Kolocouris A

    更新日期:2018-01-29 00:00:00

  • 3-Amino-chromanes and Tetrahydroquinolines as Selective 5-HT2B, 5-HT7, or σ1 Receptor Ligands.

    abstract::The phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affin...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Porter MR,Xiao H,Wang J,Smith SB,Topczewski JJ

    更新日期:2019-09-23 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


    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

  • Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists.

    abstract::Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonis...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Pasquinucci L,Parenti C,Ruiz-Cantero MC,Georgoussi Z,Pallaki P,Cobos EJ,Amata E,Marrazzo A,Prezzavento O,Arena E,Dichiara M,Salerno L,Turnaturi R

    更新日期:2020-01-28 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


    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

  • 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


    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

  • 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

  • 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


    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

  • INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ).

    abstract::A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in o...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yue EW,Li YL,Douty B,He C,Mei S,Wayland B,Maduskuie T,Falahatpisheh N,Sparks RB,Polam P,Zhu W,Glenn J,Feng H,Zhang K,Li Y,He X,Katiyar K,Covington M,Feldman P,Shin N,Wang KH,Diamond S,Li Y,Koblish HK,Hall

    更新日期:2019-10-17 00:00:00

  • Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors.

    abstract::Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bungard CJ,Williams PD,Schulz J,Wiscount CM,Holloway MK,Loughran HM,Manikowski JJ,Su HP,Bennett DJ,Chang L,Chu XJ,Crespo A,Dwyer MP,Keertikar K,Morriello GJ,Stamford AW,Waddell ST,Zhong B,Hu B,Ji T,Diamond TL,Ba

    更新日期:2017-11-13 00:00:00

  • 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 compo...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    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

    更新日期:2016-06-02 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


    authors: Bohn LM,Aubé J

    更新日期:2017-07-05 00:00:00

  • Spotlight on fluorescent biosensors-tools for diagnostics and drug discovery.

    abstract::Fluorescent biosensors constitute potent tools for probing biomolecules in their natural environment and for visualizing dynamic processes in complex biological samples, living cells, and organisms. They are well suited for highlighting molecular alterations associated with pathological disorders, thereby offering mea...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Morris MC

    更新日期:2013-12-18 00:00:00

  • Novel (64)Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases.

    abstract::We report the design, synthesis, and biological evaluation of a (64)Cu-labeled histone deacetylase (HDAC) imaging probe, which was obtained by introduction of metal chelator through click reaction of HDAC inhibitor CUDC-101 and then radiolabeled with (64)Cu. The resulting (64)Cu-labeled compound 7 ([(64)Cu]7) was iden...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Meng Q,Li F,Jiang S,Li Z

    更新日期:2013-07-25 00:00:00

  • Effectively delivering a unique hsp90 inhibitor using star polymers.

    abstract::We report the synthesis of a novel heat shock protein 90 (hsp90) inhibitor conjugated to a star polymer. Using reversible addition-fragmentation chain-transfer (RAFT) polymerization, we prepared star polymers comprised of PEG attached to a predesigned functional core. The stars were cross-linked using disulfide linker...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kim SJ,Ramsey DM,Boyer C,Davis TP,McAlpine SR

    更新日期:2013-07-25 00:00:00

  • 3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent.

    abstract::IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and p...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kerns JK,Busch-Petersen J,Fu W,Boehm JC,Nie H,Muratore M,Bullion A,Lin G,Li H,Davis R,Lin X,Lakdawala AS,Cousins R,Field R,Payne J,Miller DD,Bamborough P,Christopher JA,Baldwin I,Osborn RR,Yonchuk J,Webb E,Rum

    更新日期:2018-10-30 00:00:00

  • Discovery of a Series of Indazole TRPA1 Antagonists.

    abstract::A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed signific...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Pryde DC,Marron BE,West CW,Reister S,Amato G,Yoger K,Antonio B,Padilla K,Cox PJ,Turner J,Warmus JS,Swain NA,Omoto K,Mahoney JH,Gerlach AC

    更新日期:2017-05-18 00:00:00

  • Design, Synthesis, and X-ray Studies of Potent HIV-1 Protease Inhibitors with P2-Carboxamide Functionalities.

    abstract::The design, synthesis, biological evaluation, and X-ray structural studies are reported for a series of highly potent HIV-1 protease inhibitors. The inhibitors incorporated stereochemically defined amide-based bicyclic and tricyclic ether derivatives as the P2 ligands with (R)-hydroxyethylaminesulfonamide transition-s...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ghosh AK,Grillo A,Raghavaiah J,Kovela S,Johnson ME,Kneller DW,Wang YF,Hattori SI,Higashi-Kuwata N,Weber IT,Mitsuya H

    更新日期:2020-03-03 00:00:00

  • Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.

    abstract::Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Feng Y,Park H,Bauer L,Ryu JC,Yoon SO

    更新日期:2020-12-13 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


    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

  • Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.

    abstract::1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against P. falciparum malaria in clinical trials. Based on our previous quantitative structure...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xue J,Diao J,Cai G,Deng L,Zheng B,Yao Y,Song Y

    更新日期:2013-02-14 00:00:00

  • 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


    authors: Steadman VA

    更新日期:2018-06-04 00:00:00

  • Design, synthesis, and biological evaluation of ring-constrained novobiocin analogues as hsp90 C-terminal inhibitors.

    abstract::Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not ind...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Garg G,Zhao H,Blagg BS

    更新日期:2014-12-12 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

  • Multicomponent Synthesis and Biological Evaluation of a Piperazine-Based Dopamine Receptor Ligand Library.

    abstract::A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Stucchi M,Gmeiner P,Huebner H,Rainoldi G,Sacchetti A,Silvani A,Lesma G

    更新日期:2015-06-23 00:00:00

  • Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group.

    abstract::The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substitute...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu J,Yu Y,Kelly J,Sha D,Alhassan AB,Yu W,Maletic MM,Duffy JL,Klein DJ,Holloway MK,Carroll S,Howell BJ,Barnard RJO,Wolkenberg S,Kozlowski JA

    更新日期:2020-10-13 00:00:00

  • Small Macrocycles As Highly Active Integrin α2β1 Antagonists.

    abstract::Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar r...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Halland N,Blum H,Buning C,Kohlmann M,Lindenschmidt A

    更新日期:2014-01-10 00:00:00

  • Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.

    abstract::In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular model...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wu WL,Hao J,Domalski M,Burnett DA,Pissarnitski D,Zhao Z,Stamford A,Scapin G,Gao YD,Soriano A,Kelly TM,Yao Z,Powles MA,Chen S,Mei H,Hwa J

    更新日期:2016-03-12 00:00:00

  • Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist.

    abstract::We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in v...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xue CB,Wang A,Han Q,Zhang Y,Cao G,Feng H,Huang T,Zheng C,Xia M,Zhang K,Kong L,Glenn J,Anand R,Meloni D,Robinson DJ,Shao L,Storace L,Li M,Hughes RO,Devraj R,Morton PA,Rogier DJ,Covington M,Scherle P,Diamond

    更新日期:2011-10-05 00:00:00