当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Synthesis and pharmacological evaluation of bivalent tethered ligands to target the mGlu2/4 heterodimeric receptor results in a compound with mGlu2/2 homodimer selectivity.

Synthesis and pharmacological evaluation of bivalent tethered ligands to target the mGlu2/4 heterodimeric receptor results in a compound with mGlu2/2 homodimer selectivity.

Abstract：

:This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu2/4 heterodimeric receptor that exists in the CNS and may represent a novel drug target to modulate the glutamatergic system. As multiple hit-to-lead campaigns from HTS hits failed to produce selective small molecule mGlu2/4 heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu2 PAM at one terminus and an mGlu4 PAM at the other). Utilizing G protein-Inwardly Rectifying Potassium (GIRK) channel functional assays, we found that the tethered ligands displayed PAM activity in a cell line co-expressing both mGlu2 and mGlu4 but also in cells expressing mGlu2 or mGlu4 alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu2/4 heterodimers; however, another compound displayed 75-fold preference for the mGlu2/2 homodimer over heterodimeric mGlu2/4 or homomeric mGlu4/4. This work highlights the development of mGlu receptor PAMs with homodimer/heterodimer preference and expands the potential for PAMs as tethered ligands beyond the more classical antagonists and NAMs.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Fulton MG,Loch MT,Rodriguez AL,Lin X,Javitch JA,Conn PJ,Niswender CM,Lindsley CW

doi

10.1016/j.bmcl.2020.127212

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

127212

issue

13

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30312-7

journal_volume

30

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents.

    abstract：:The Gram-negative bacterium Acinetobacter baumannii is an opportunistic pathogen in humans and infections are poorly treated by current therapy. Recent emergence of multi-drug resistant strains and the lack of new antibiotics demand an immediate action for development of new anti-Acinetobacter agents. To this end, oxi...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.11.020

    authors： Rubin H,Selwood T,Yano T,Weaver DG,Loughran HM,Costanzo MJ,Scott RW,Wrobel JE,Freeman KB,Reitz AB

    更新日期：2015-01-15 00:00:00

  • Discovery of 5-hydroxyalkyl-4-phenylpyridines as a new class of glucagon receptor antagonists.

    abstract：:5-Hydroxyalkyl-4-phenylpyridines have been identified as a novel class of glucagon antagonists with potential utility for the treatment of diabetes. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure-activity relationships led to the discovery of a potent antago...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00766-1

    authors： Ladouceur GH,Cook JH,Doherty EM,Schoen WR,MacDougall ML,Livingston JN

    更新日期：2002-02-11 00:00:00

  • A non-crosslinking platinum-acridine hybrid agent shows enhanced cytotoxicity compared to clinical BCNU and cisplatin in glioblastoma cells.

    abstract：:Using clonogenic survival assays, we demonstrated that a new platinum-acridine hybrid agent, PT-ACRAMTU, is cytotoxic in SNB19 and U87MG glioblastoma cells at low-micromolar concentrations. PT-ACRAMTU is more cytotoxic than ACRAMTU (the platinum-free acridine), acts in a time and dose dependent manner, and appears to ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.10.049

    authors： Hess SM,Anderson JG,Bierbach U

    更新日期：2005-01-17 00:00:00

  • Synthesis and anti-Candida activity of novel 2-hydrazino-1,3-thiazole derivatives.

    abstract：:Eighteen new hydrazino-1,3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp. Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains. Introduction of a (S)-2-aminoethyl...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.01.039

    authors： Maillard LT,Bertout S,Quinonéro O,Akalin G,Turan-Zitouni G,Fulcrand P,Demirci F,Martinez J,Masurier N

    更新日期：2013-03-15 00:00:00

  • A conformationally constrained inhibitor with an enhanced potency for β-tryptase and stability against semicarbazide-sensitive amine oxidase (SSAO).

    abstract：:A novel β-tryptase inhibitor with a basic benzylamine P1 group, a piperidine-amide linker, and a substituted indole P4 group was discovered. A substitution at 4-indole position was introduced to constrain the conformational flexibility of the inhibitor to the bioactive conformation exhibited by X-ray structures so tha...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.08.141

    authors： Liang G,Choi-Sledeski YM,Poli G,Chen X,Shum P,Minnich A,Wang Q,Tsay J,Sides K,Cairns J,Stoklosa G,Nieduzak T,Zhao Z,Wang J,Vaz RJ

    更新日期：2010-11-15 00:00:00

  • Recent advances in peptidomimetics antagonists targeting estrogen receptor α-coactivator interaction in cancer therapy.

    abstract：:Estrogen receptor α (ERα) is a crucial target for ERα positive breast cancer treatment. Previous drug discovery efforts were focused on developing inhibitors that targeted the canonical ligand binding pockets of the ligand binding domain (LBD) of ERα. However, significant percentage of patients developed cancer relaps...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章,评审

    doi：10.1016/j.bmcl.2018.05.062

    authors： Qin W,Xie M,Qin X,Fang Q,Yin F,Li Z

    更新日期：2018-09-15 00:00:00

  • Interaction of heterocyclic thiols/thiones eliminated from cephalosporins with iodine and its biological implications.

    abstract：:Hydrolysis of beta-lactam antibiotics by beta-lactamases (e.g., metallo-beta-lactamase, mbetal) is one of the major bacterial defense systems. These enzymes can catalyze the hydrolysis of a variety of antibiotics including the latest generation of cephalosporins, cephamycins and imipenem. It is shown in this paper tha...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.04.087

    authors： Tamilselvi A,Mugesh G

    更新日期：2010-06-15 00:00:00

  • Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity.

    abstract：:Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.04.036

    authors： Chen C,Chen Y,Pontillo J,Guo Z,Huang CQ,Wu D,Madan A,Chen T,Wen J,Xie Q,Tucci FC,Rowbottom M,Zhu YF,Wade W,Saunders J,Bozigian H,Struthers RS

    更新日期：2008-06-01 00:00:00

  • Pterin-sulfa conjugates as dihydropteroate synthase inhibitors and antibacterial agents.

    abstract：:The sulfonamide class of antibiotics has been in continuous use for over 70years. They are thought to act by directly inhibiting dihydropteroate synthase (DHPS), and also acting as prodrugs that sequester pterin pools by forming dead end pterin-sulfonamide conjugates. In this study, eight pterin-sulfonamide conjugates...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.07.006

    authors： Zhao Y,Shadrick WR,Wallace MJ,Wu Y,Griffith EC,Qi J,Yun MK,White SW,Lee RE

    更新日期：2016-08-15 00:00:00

  • Chroman-3-amides as potent Rho kinase inhibitors.

    abstract：:Inhibition of Rho kinase (ROCK) is an attractive strategy for the treatment of diseases such as hypertension, glaucoma, and cancer. Here we report chroman-3-amides as highly potent ROCK inhibitors with sufficient kinase selectivity, excellent cell activity, good microsomal stability, and desirable pharmacokinetic prop...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.10.080

    authors： Chen YT,Bannister TD,Weiser A,Griffin E,Lin L,Ruiz C,Cameron MD,Schürer S,Duckett D,Schröter T,LoGrasso P,Feng Y

    更新日期：2008-12-15 00:00:00

  • Synthesis and antitumor activity of cyclodepsipeptide zygosporamide and its analogues.

    abstract：:The synthesis and structure-activity relationships of zygosporamide, a known potent and selective cytotoxic natural product against SF-268 and RXF 393 cell lines, are described. The potencies of the synthetic zygosporamide are similar to those reported for the natural product toward all cancer cell lines examined with...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.06.066

    authors： Wang Y,Zhang F,Zhang Y,Liu JO,Ma D

    更新日期：2008-08-01 00:00:00

  • Synthesis of novel 5,6-dehydrokawain analogs as osteogenic inducers and their action mechanisms.

    abstract：:An imbalance between bone resorption by osteoclasts and bone formation by osteoblasts can cause bone loss and bone-related disease. In a previous search for natural products that increase osteogenic activity, we found that 5,6-dehydrokawain (1) from Alpinia zerumbet promotes osteoblastogenesis. In this study, we synth...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2017.04.016

    authors： Kumagai M,Nishikawa K,Mishima T,Yoshida I,Ide M,Koizumi K,Nakamura M,Morimoto Y

    更新日期：2017-06-01 00:00:00

  • Pyrazole NNRTIs 1: design and initial optimisation of a novel template.

    abstract：:The design and synthesis of a novel series of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on a pyrazole template is described. These compounds are active against wild type reverse transcriptase (RT) and retain activity against clinically important mutants. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.08.039

    authors： Mowbray CE,Burt C,Corbau R,Perros M,Tran I,Stupple PA,Webster R,Wood A

    更新日期：2009-10-01 00:00:00

  • Novel 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-one derivatives as potential anti-cancer agents.

    abstract：:A novel series of 3,5,6-trisubstituted pyrazolo[4,3-d]pyrimidin-7-one derivatives, especially 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-ones were synthesized and evaluated for their in vitro anticancer activities against various human cancer cell lines. The inhibitory activities for several kinases have also been ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.01.029

    authors： Devegowda VN,Kim JH,Han KC,Yang EG,Choo H,Pae AN,Nam G,Choi KI

    更新日期：2010-03-01 00:00:00

  • Synthesis and biological activities of NB-506 analogues: Effects of the positions of two hydroxyl groups at the indole rings.

    abstract：:In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 res...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00595-8

    authors： Ohkubo M,Nishimura T,Honma T,Nishimura I,Ito S,Yoshinari T,Suda HA,Morishima H,Nishimura S

    更新日期：1999-12-06 00:00:00

  • New insights into pradimicin biosynthesis revealed by two O-methyltransferases.

    abstract：:Pradimicins are a group of antiviral and antifungal natural products from Actinomadura hibisca. Two putative O-methyltransferase genes, pdmF and pdmT, are present in the pradimicin biosynthetic gene cluster. However, there is only one methoxy group (11-OCH3) in pradimicins. Through heterologous expression and in vitro...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2017.05.068

    authors： Xu F,Napan K,Zhang S,Gladwin T,Takemoto J,Zhan J

    更新日期：2017-08-01 00:00:00

  • Aminopyrrolidineamide inhibitors of site-1 protease.

    abstract：:The discovery and efficacy of a series of potent aminopyrrolidineamide-based inhibitors of sterol regulatory element binding protein site-1 protease is described. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.06.031

    authors： Hay BA,Abrams B,Zumbrunn AY,Valentine JJ,Warren LC,Petras SF,Shelly LD,Xia A,Varghese AH,Hawkins JL,Van Camp JA,Robbins MD,Landschulz K,Harwood HJ Jr

    更新日期：2007-08-15 00:00:00

  • Chlorin e6-cholesterol conjugate and its copper complex. Simple synthesis and entrapping in phospholipid vesicles.

    abstract：:Synthesis of 13'[(cholest-5-en)-3beta-yloxyethoxycarbamoyl]-chlorin e6 starting from methylpheophorbide and 3beta(2-hydroxy)-ethoxycholest-5-ene is presented, as well as the preparation of related copper complex. Both conjugates obtained may be simply incorporated in phosphatidyl choline vesicles. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.03.041

    authors： Nikolaeva IA,Misharin AY,Ponomarev GV,Timofeev VP,Tkachev YV

    更新日期：2010-05-01 00:00:00

  • Discovery of fused 5,6-bicyclic heterocycles as γ-secretase modulators.

    abstract：:We herein report the discovery of four series of fused 5,6-bicyclic heterocycles as γ-secretase modulators. Synthesis and SAR of these series are discussed. These compounds represent a new class of γ-secretase modulators that demonstrate moderate to good in vitro potency in inhibiting Aβ(42) production. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.12.012

    authors： Qin J,Dhondi P,Huang X,Mandal M,Zhao Z,Pissarnitski D,Zhou W,Aslanian R,Zhu Z,Greenlee W,Clader J,Zhang L,Cohen-Williams M,Jones N,Hyde L,Palani A

    更新日期：2011-01-15 00:00:00

  • Small molecule inhibitors of HIV RT Ribonuclease H.

    abstract：:Two classes of compounds, thiocarbamates 1 and triazoles 2, have been identified as HIV RT RNase H inhibitors using a novel FRET-based HTS assay. The potent analogs in each series exhibited selectivity and were active in cell-based assays. In addition, saturable, 1:1 stoichiometric binding to target was established an...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.10.043

    authors： Di Grandi M,Olson M,Prashad AS,Bebernitz G,Luckay A,Mullen S,Hu Y,Krishnamurthy G,Pitts K,O'Connell J

    更新日期：2010-01-01 00:00:00

  • The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations.

    abstract：:Approaches to improve the efficiency of molecular optimizations have received great attention and numerous efficiency metrics have been introduced to assist in this effort. Optimization of properties is equally important to optimization of potency and therefore these metrics contain potency versus property calculation...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.08.030

    authors： Shultz MD

    更新日期：2013-11-01 00:00:00

  • Synthesis and biological study of medicinally important Mannich bases derived from 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a pentahydroxy naphthacene carboxamide.

    abstract：:The paper describes synthesis and antibacterial study of biologically active Mannich bases of carboxamide derivative employing Mannich reaction of 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a pentahydroxy naphthacene carboxamide with various sulfonamides/secondary amines . They were analysed by eleme...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2006.11.001

    authors： Joshi S,Manikpuri AD,Tiwari P

    更新日期：2007-02-01 00:00:00

  • Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors.

    abstract：:Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2020.127048

    authors： Ma X,Diao Y,Ge H,Xu F,Zhu L,Zhao Z,Li H

    更新日期：2020-04-15 00:00:00

  • The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase.

    abstract：:Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.04.015

    authors： Ren L,Ahrendt KA,Grina J,Laird ER,Buckmelter AJ,Hansen JD,Newhouse B,Moreno D,Wenglowsky S,Dinkel V,Gloor SL,Hastings G,Rana S,Rasor K,Risom T,Sturgis HL,Voegtli WC,Mathieu S

    更新日期：2012-05-15 00:00:00

  • Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors.

    abstract：:EZH2 is the core subunit of Polycomb repressive complex 2 catalyzing the methylation of histone H3 lysine-27 and closely involved in tumorigenesis. To discover small molecule inhibitors for EZH2 methyltransferase activity, we performed an inhibitor screen with catalytically active EZH2 protein complex and identified t...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.04.010

    authors： Woo J,Kim HY,Byun BJ,Chae CH,Lee JY,Ryu SY,Park WK,Cho H,Choi G

    更新日期：2014-06-01 00:00:00

  • Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions.

    abstract：:SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ(40) lowering model....

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.03.094

    authors： Su J,Tang H,McKittrick BA,Xu R,Clader JW,Greenlee WJ,Hyde L,Zhang L

    更新日期：2011-06-01 00:00:00

  • Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors.

    abstract：:Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstr...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.05.129

    authors： Zhang Z,Kodumuru V,Sviridov S,Liu S,Chafeev M,Chowdhury S,Chakka N,Sun J,Gauthier SJ,Mattice M,Ratkay LG,Kwan R,Thompson J,Cutts AB,Fu J,Kamboj R,Goldberg YP,Cadieux JA

    更新日期：2012-08-01 00:00:00

  • Discovery of phenanthridine analogues as novel chemical probes disrupting the binding of DNA to ΔFosB homodimers and ΔFosB/JunD heterodimers.

    abstract：:The transcription factor ΔFosB accumulates in response to chronic insults such as drugs of abuse, L-3,4-dihydroxyphenylalanine (l-DOPA) or stress in specific regions of the brain, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, dyskinesia, and depression. Thus, small mole...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2020.127300

    authors： Li Y,Liu Z,Aglyamova G,Chen J,Chen H,Bhandari M,White MA,Rudenko G,Zhou J

    更新日期：2020-08-15 00:00:00

  • Quantitating the concentration of Py-Im polyamide-fluorescein conjugates in live cells.

    abstract：:Quantitative fluorescence-based methods have been developed to determine the nuclear concentration of polyamide-fluorescein conjugates in cell culture. Confocal laser scanning microscopy and flow cytometry techniques are utilized to plot calibration curves, from which the nuclear concentration can be interpolated. Upo...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.05.063

    authors： Hsu CF,Dervan PB

    更新日期：2008-11-15 00:00:00

  • Synthesis and cytotoxic activity of novel tetrahydrobenzodifuran-imidazolium salt derivatives.

    abstract：:The synthesis of a series of novel 4-substituted 2,3,6,7-tetrahydrobenzo [1,2-b;4,5-b']difuran-1H-imidazolium salts is presented. The biological properties of the compounds were evaluated in vitro against a panel of human tumor cell lines. Results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-benzimidazole r...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2017.02.053

    authors： Zhang CB,Liu Y,Liu ZF,Duan SZ,Li MY,Chen W,Li Y,Zhang HB,Yang XD

    更新日期：2017-04-15 00:00:00