4-Substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with superior pharmacological and pharmacokinetic parameters.


:A novel class of 4-substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. These molecules also exhibit superior pharmacological and pharmacokinetic parameters, relative to all GlyT1 inhibitors of the spiropiperidine family, culminating in the identification of 16b with an oral bioavailability of approximately 60%. In addition, a straightforward two-step procedure for the assembly of the target molecules is also presented.


Bioorg Med Chem Lett


Alberati D,Hainzl D,Jolidon S,Kurt A,Pinard E,Thomas AW,Zimmerli D




Has Abstract


2006-08-15 00:00:00














  • Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands--part II.

    abstract::A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectiv...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ward SE,Eddershaw P,Flynn ST,Gordon L,Lovell PJ,Moore SH,Scott CM,Smith PW,Thewlis KM,Wyman PA

    更新日期:2009-01-15 00:00:00

  • Synthesis of novel keto-ACE analogues as domain-selective angiotensin I-converting enzyme inhibitors.

    abstract::Novel analogues of the angiotensin I-converting enzyme (ACE) inhibitor keto-ACE were synthesized via a facile Horner-Emmons olefination of a phosphonoketone precursor with ethyl glyoxylate. Introduction of a bulky aromatic tryptophan at the P(2)(') position of keto-ACE resulted in a significant increase in C-domain-se...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nchinda AT,Chibale K,Redelinghuys P,Sturrock ED

    更新日期:2006-09-01 00:00:00

  • A novel solid support for synthesis of oligonucleotide 3'-phosphorothioate monoesters.

    abstract::A new reagent immobilized on solid support allowing for solid-phase synthesis of oligonucleotides with a 3'-terminal phosphorothioate monoester is described. The support is compatible with phosphoramidite chemistry for automated oligonucleotide synthesis. Final deprotection with ammonia under standard conditions leads...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cheruvallath ZS,Cole DL,Ravikumar VT

    更新日期:2003-01-20 00:00:00

  • Antitumor platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with dicarboxylates as leaving groups.

    abstract::Four platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with different bidentate dicarboxylates (1 oxalate, 2 malonate, 3 1,1-cyclobutanedicarboxylate and 4 3-hydroxy-1,1-cyclobutanedicarboxylate) as leaving groups were synthesized and characterized by elemental analyses, IR and (1)HNMR spectra together w...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xu G,Zhao J,Gou S,Pang J

    更新日期:2015-01-15 00:00:00

  • Synthesis of enamino-2-oxindoles via conjugate addition between α-azido ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis inducing studies.

    abstract::A facile method for the construction of double bond between 3-ylidene oxindoles and α-azido ketones has been successfully accomplished with a mild base. This method features azido reduction with concomitant double bond formation to provide the new class of bioactive enamino-2-oxindoles. These new compounds were screen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kumar NP,Vanjari Y,Thatikonda S,Pooladanda V,Sharma P,Sridhar B,Godugu C,Kamal A,Shankaraiah N

    更新日期:2018-12-01 00:00:00

  • 5-Propynylamino alpha-deoxyuridine promotes DNA duplex stabilization of anionic and neutral but not cationic alpha-oligonucleotides.

    abstract::Incorporation of 5-propynylamino and 5-propynyl alpha-2'-deoxyuridine into alpha-oligonucleotides (alpha-ON) allows high-affinity targeting of complementary DNA for alpha-ON with anionic and neutral backbone but not for cationic alpha-ON, revealing clues on the role of the amino group of the propynylamino on the forma...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Deglane G,Morvan F,Debart F,Vasseur JJ

    更新日期:2007-02-15 00:00:00

  • 1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives.

    abstract::Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hall A,Brown SH,Chessell IP,Chowdhury A,Clayton NM,Coleman T,Giblin GM,Hammond B,Healy MP,Johnson MR,Metcalf A,Michel AD,Naylor A,Novelli R,Spalding DJ,Sweeting J,Winyard L

    更新日期:2007-02-15 00:00:00

  • An efficient synthesis of 3-OBn-6β,14-epoxy-bridged opiates from naltrexone and identification of a related dual MOR inverse agonist/KOR agonist.

    abstract::In an effort to better understand the conformational preferences that inform the biological activity of naltrexone and related naltrexol derivatives, a new synthesis of the restricted analog 3-OBn-6β,14-epoxymorphinan 4 is described. 4 was synthesized starting from naltrexone in 50% overall yield, proceeding through t...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Martin DJ,FitzMorris PE,Li B,Ayestas M,Sally EJ,Dersch CM,Rothman RB,Deveau AM

    更新日期:2012-11-15 00:00:00

  • Anti-inflammatory property of the urinary metabolites of nobiletin in mouse.

    abstract::Nobiletin, a major component of polymethoxyflavones in citrus fruits, has a broad spectrum of health beneficial properties including anti-inflammatory and anti-carcinogenic activities. The metabolite identification of nobiletin in mouse urine has concluded that it undergoes mono-demethylation (3'- and 4'-demethylnobil...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li S,Sang S,Pan MH,Lai CS,Lo CY,Yang CS,Ho CT

    更新日期:2007-09-15 00:00:00

  • Synthesis of some novel phosphorylated and thiophosphorylated benzimidazoles and benzothiazoles and their evaluation for larvicidal potential to Aedes albopictus and Culex quinquefasciatus.

    abstract::Series of benzimidazole and benzothiazole linked phosphoramidates and phosphoramidothioates (5a-j) and benzimidazole linked phenylphosphoramidates and phenylphosphoramidothioates (10a-e) were synthesized. The title compounds were preliminary screened for mosquito larvicidal properties against Aedes albopictus and Cule...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bandyopadhyay P,Sathe M,Tikar SN,Yadav R,Sharma P,Kumar A,Kaushik MP

    更新日期:2014-07-01 00:00:00

  • The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold.

    abstract::Glucokinase is a key enzyme in glucose homeostasis since it phosphorylates glucose to give glucose-6-phosphate, which is the first step in glycolysis. GK activators have been proven to lower blood-glucose, and therefore have potential as treatments for type 2 diabetes. Here the discovery of pyrazolopyrimidine GKAs is ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bonn P,Brink DM,Fägerhag J,Jurva U,Robb GR,Schnecke V,Svensson Henriksson A,Waring MJ,Westerlund C

    更新日期:2012-12-15 00:00:00

  • Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).

    abstract::Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecule...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Moffett K,Konteatis Z,Nguyen D,Shetty R,Ludington J,Fujimoto T,Lee KJ,Chai X,Namboodiri H,Karpusas M,Dorsey B,Guarnieri F,Bukhtiyarova M,Springman E,Michelotti E

    更新日期:2011-12-01 00:00:00

  • Cardioprotective potential of N,α-L-rhamnopyranosyl vincosamide, an indole alkaloid, isolated from the leaves of Moringa oleifera in isoproterenol induced cardiotoxic rats: in vivo and in vitro studies.

    abstract::Hitherto unknown protective effect of N,α-L-rhamnopyranosyl vincosamide (VR), isolated from Moringa oleifera leaves in isoproterenol (ISO)-induced cardiac toxicity was evaluated in rats. Oral administration of VR at 40 mg/kg for 7 days markedly reduced the ISO-induced increase in the levels of serum cardiac markers su...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Panda S,Kar A,Sharma P,Sharma A

    更新日期:2013-02-15 00:00:00

  • Synthesis and neurotrophic activity of nonimmunosuppressant cyclosporin A derivatives.

    abstract::In order to exploit cyclophilin as a potential target for neurological drug design, we demonstrate in this presentation that several nonimmunosuppressant analogues of cyclosporin A, modified at the various positions in the 'effector' domain, are equipotent nerve growth agents compared to cyclosporin A. Our results sug...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wei L,Steiner JP,Hamilton GS,Wu YQ

    更新日期:2004-09-06 00:00:00

  • Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure.

    abstract::We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Harada K,Mizukami J,Watanabe T,Mori G,Ubukata M,Suwa K,Fukuda S,Negoro T,Sato M,Inaba T

    更新日期:2019-02-01 00:00:00

  • Polarization in the structures of uracil and thiouracils: Implication for binding with orotidine 5'-monophosphate decarboxylase.

    abstract::The structures of the uracil and thiouracils were examined using NMR spectroscopy and crystal structure data when available. The relationships between the extent of polarization and the C5-C6 bond length as well as the H5-H6 coupling constants were probed. It was found that the bond length and coupling constants corre...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Huang S,Gronert S,Wu W

    更新日期:2011-11-01 00:00:00

  • Probing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitors.

    abstract::Human isoprenylcysteine carboxyl methyltransferase (hIcmt) is a promising anticancer target as it is important for the post-translational modification of oncogenic Ras proteins. We herein report the synthesis and biochemical activity of 41 farnesyl-cysteine based analogs versus hIcmt. We have demonstrated that the ami...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Majmudar JD,Hahne K,Hrycyna CA,Gibbs RA

    更新日期:2011-05-01 00:00:00

  • 6-arylamino-5,8-quinolinediones and 7-arylamino-5,8-isoquinolinediones as inhibitors of endothelium-dependent vasorelaxation.

    abstract::6-Arylamino-5,8-quinolinediones 3 and 7-arylamino-5,8-isoquinolinediones 4 were synthesized as inhibitors of endothelium-dependent vasorelaxation. The quinones inhibited the vasorelaxation of rat aorta with the endothelium. Among them, the quinones 3a, 3b, 3f, 4b, 4d and 4g strongly inhibited the vasorelaxation. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ryu CK,Jung SH,Lee JA,Kim HJ,Lee SH,Chung JH

    更新日期:1999-09-06 00:00:00

  • Design, synthesis, and antibacterial activity of 2,5-dihydropyrrole formyl hydroxyamino derivatives as novel peptide deformylase inhibitors.

    abstract::The synthesis and antibacterial activity of 2,5-dihydropyrrole formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated, and some of these derivatives showed better in vitro antibacterial activity than existing drugs, including penicillin, ciprofloxacin, vancomycin...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shi W,Duan Y,Qian Y,Li M,Yang L,Hu W

    更新日期:2010-06-15 00:00:00

  • One-class classification as a novel method of ligand-based virtual screening: the case of glycogen synthase kinase 3β inhibitors.

    abstract::A virtual screening system based on one-class classification with molecular fingerprints as descriptors is developed and tested on a series of 1226 inhibitors and 209 noninhibitors of glycogen synthase kinase 3β (GSK-3β). The suggested system outperforms the ones based on pharmacophore hypothesis and molecular docking...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Karpov PV,Osolodkin DI,Baskin II,Palyulin VA,Zefirov NS

    更新日期:2011-11-15 00:00:00

  • Tritium-labeled (E,E)-2,5-bis(4'-hydroxy-3'-carboxystyryl)benzene as a probe for β-amyloid fibrils.

    abstract::Accumulation of Aβ in the brains of Alzheimer disease (AD) patients reflects an imbalance between Aβ production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Aβ40 and Aβ42 peptides that a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Matveev SV,Kwiatkowski S,Sviripa VM,Fazio RC,Watt DS,LeVine H 3rd

    更新日期:2014-12-01 00:00:00

  • Radiosynthesis and in vivo tumor uptake of 2-deoxy-2-[(18)F]fluoro-myo-inositol.

    abstract::Inositols play an important role in membrane lipid metabolism and mitogenic signaling of most cancer cells. There is paucity of data on the distribution of radiolabelled inositols. Based on work previously carried out on 1-deoxy-1-[(18)F]fluoro-scyllo-inositol ([(18)F]2), we began a program of work to label myo-inosit...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Carroll L,Perumal M,Vasdev N,Robins E,Aboagye EO

    更新日期:2012-10-01 00:00:00

  • Nanoencapsulation of triterpene 3β,6β,16β-trihydroxylup-20(29)-ene from Combretum leprosum as strategy to improve its cytotoxicity against cancer cell lines.

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Silva-Filho CJA,Freitas PGC,Oliveira FCE,Barbosa FG,Oliveira MCF,Eloy JO,Pessoa C,Mafezoli J

    更新日期:2020-10-15 00:00:00

  • Compelling P1 substituent affect on metalloprotease binding profile enables the design of a novel cyclohexyl core scaffold with excellent MMP selectivity and HER-2 sheddase inhibition.

    abstract::A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Burns DM,Li YL,Shi E,He C,Xu M,Zhuo J,Zhang C,Qian DQ,Li Y,Wynn R,Covington MB,Katiyar K,Marando CA,Fridman JS,Scherle P,Friedman S,Metcalf B,Yao W

    更新日期:2009-07-01 00:00:00

  • Novel thiazolidinedione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-γ activators.

    abstract::Benzylidene-2,4-thiazolidinedione derivatives with substitutions at both the ortho and para-positions of the phenyl group were synthesized as PTP1B inhibitors with IC(50) values in a low micromolar range. Compound 18l, the lowest, bore an IC(50) of 1.3 μM. In a peroxisome proliferator-activated receptor-γ (PPAR-γ) pro...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bhattarai BR,Kafle B,Hwang JS,Ham SW,Lee KH,Park H,Han IO,Cho H

    更新日期:2010-11-15 00:00:00

  • N-Benzyloxycarbonyl-S-(2,4-dinitrophenyl)glutathione dibutyl diester is inhibitory to melarsoprol resistant cell lines overexpressing the T. bruceiMRPA transporter.

    abstract::A series of glutathione derivatives 1-4, modified at the N,S and/or COOH sites, with in vitro antitrypanosomal activity were tested against bloodstream form Trypanosoma brucei 247 wild type and a T. b. brucei 247 strain over-expressing the multiple drug resistance protein (MRPA) by 50-100x to assess the susceptibility...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Alibu VP,Daunes S,D'Silva C

    更新日期:2013-08-01 00:00:00

  • Facile and efficient one-pot synthesis of 4beta-arylaminopodophyllotoxins: synthesis of DNA topoisomerase II inhibitors (NPF and W-68).

    abstract::A series of 4beta-arylamino-4'-O-demethylepipodophyllotoxins and 4beta-arylaminoepipodophyllotoxins have been synthesized with significant stereoselectivity and improved yields by employing the methanesulphonic acid/sodium iodide reagent system. Compounds NPF. W-68 and other DNA topoisomerase II inhibitors are prepare...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kamal A,Laxman N,Ramesh G

    更新日期:2000-09-18 00:00:00

  • A new class of potent non-imidazole H(3) antagonists: 2-aminoethylbenzofurans.

    abstract::2-aminoethylbenzofurans constitute a new class of H(3) antagonists that are more rotationally constrained than most previously reported H(3) antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cowart M,Pratt JK,Stewart AO,Bennani YL,Esbenshade TA,Hancock AA

    更新日期:2004-02-09 00:00:00

  • Tetradehydrohalicyclamine B, a new proteasome inhibitor from the marine sponge Acanthostrongylophora ingens.

    abstract::A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration o...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kato H,El-Desoky AH,Takeishi Y,Nehira T,Angkouw ED,Mangindaan REP,de Voogd NJ,Tsukamoto S

    更新日期:2019-01-01 00:00:00

  • 2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A(2A) antagonists with reduced hERG liability.

    abstract::In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG l...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Moorjani M,Zhang X,Chen Y,Lin E,Rueter JK,Gross RS,Lanier MC,Tellew JE,Williams JP,Lechner SM,Malany S,Santos M,Ekhlassi P,Castro-Palomino JC,Crespo MI,Prat M,Gual S,Díaz JL,Saunders J,Slee DH

    更新日期:2008-02-15 00:00:00