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.

Abstract:

: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.

journal_name

Bioorg Med Chem Lett

authors

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

doi

10.1016/j.bmcl.2006.05.063

subject

Has Abstract

pub_date

2006-08-15 00:00:00

pages

4321-5

issue

16

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(06)00601-9

journal_volume

16

pub_type

杂志文章
  • Design and synthesis of new bis-pyridinium oxime reactivators for acetylcholinesterase inhibited by organophosphorous nerve agents.

    abstract::New bis-pyridinium oxime reactivators connected with a CH(2)CH(2)OCH(2)CH(2) linker between two pyridinium rings were designed and synthesized. In the test of their potency to reactivate AChE inhibited by cyclosarin, the bis-pyridinium oxime 6b achieved reactivation potency higher than 10% at the lower concentration 1...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.03.060

    authors: Kim TH,Kuca K,Jun D,Jung YS

    更新日期:2005-06-02 00:00:00

  • Anticonvulsant and analgesic in neuropathic pain activity in a group of new aminoalkanol derivatives.

    abstract::As part of the presented research, thirteen new aminoalkanol derivatives were designed and obtained by chemical synthesis. In vivo studies (mice, i.p.) showed anticonvulsant activity (MES) of nine compounds, and in the case of one compound (R,S-trans-2-((2-(2,3,5-trimethylphenoxy)ethyl)amino)cyclohexan-1-ol, 4) both a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2020.127325

    authors: Pańczyk K,Rapacz A,Furgała-Wojas A,Sałat K,Koczurkiewicz-Adamczyk P,Łucjanek M,Skiba-Kurek I,Karczewska E,Sowa A,Żelaszczyk D,Siwek A,Popiół J,Pękala E,Marona H,Waszkielewicz A

    更新日期:2020-08-15 00:00:00

  • Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.

    abstract::Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.09.074

    authors: Govek SP,Nagasawa JY,Douglas KL,Lai AG,Kahraman M,Bonnefous C,Aparicio AM,Darimont BD,Grillot KL,Joseph JD,Kaufman JA,Lee KJ,Lu N,Moon MJ,Prudente RY,Sensintaffar J,Rix PJ,Hager JH,Smith ND

    更新日期:2015-11-15 00:00:00

  • A naturally occurring brominated furanone covalently modifies and inactivates LuxS.

    abstract::Halogenated furanones, a group of natural products initially isolated from marine red algae, are known to inhibit bacterial biofilm formation, swarming, and quorum sensing. However, their molecular targets and the precise mode of action remain elusive. Herein, we show that a naturally occurring brominated furanone cov...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.08.095

    authors: Zang T,Lee BW,Cannon LM,Ritter KA,Dai S,Ren D,Wood TK,Zhou ZS

    更新日期:2009-11-01 00:00:00

  • Modulating the development of E. coli biofilms with 2-aminoimidazoles.

    abstract::The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the bes...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.08.075

    authors: Reed CS,Huigens RW 3rd,Rogers SA,Melander C

    更新日期:2010-11-01 00:00:00

  • Aromatic glycosyl disulfide derivatives: evaluation of their inhibitory activities against Trypanosoma cruzi.

    abstract::Aromatic oligovalent glycosyl disulfides and some diglycosyl disulfides were tested against three different Trypanosoma cruzi strains. Di-(β-D-galactopyranosyl-dithiomethylene) benzenes 2b and 4b proved to be the most active derivatives against all three strains of cell culture-derived trypomastigotes with IC50 values...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 信件

    doi:10.1016/j.bmcl.2013.04.030

    authors: Gutiérrez B,Muñoz C,Osorio L,Fehér K,Illyés TZ,Papp Z,Kumar AA,Kövér KE,Sagua H,Araya JE,Morales P,Szilágyi L,González J

    更新日期:2013-06-15 00:00:00

  • Synthesis and antiinflammatory activity of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide.

    abstract::Nineteen new 2-pyrazoline bearing benzenesulfonamide derivatives were synthesized by condensing chalcones with 4-hydrazinonbenzenesulfonamide hydrochloride. Their chemical structures were proved by means of IR, (1)H NMR, (13)C NMR, mass spectroscopic and elemental analyses data. These compounds were tested at dose of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.10.105

    authors: Rathish IG,Javed K,Ahmad S,Bano S,Alam MS,Pillai KK,Singh S,Bagchi V

    更新日期:2009-01-01 00:00:00

  • Synthesis of conjugates between oxazolidinone antibiotics and a pyochelin analogue.

    abstract::Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium responsible for severe infections, and it is naturally resistant to many clinically approved antibiotic families. Oxazolidinone antibiotics are active against many Gram-positive bacteria, but are inactive against P. aeruginosa. Increasing the uptake of oxa...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.09.039

    authors: Paulen A,Hoegy F,Roche B,Schalk IJ,Mislin GLA

    更新日期:2017-11-01 00:00:00

  • 2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation.

    abstract::Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents in cis-imidazoline core for biological activity of nutlin family...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2019.06.007

    authors: Bazanov DR,Pervushin NV,Savitskaya VY,Anikina LV,Proskurnina MV,Lozinskaya NA,Kopeina GS

    更新日期:2019-08-15 00:00:00

  • Tanzawaic acid derivatives from a marine isolate of Penicillium sp. (SF-6013) with anti-inflammatory and PTP1B inhibitory activities.

    abstract::Chemical investigation of a marine-derived fungus Penicillium sp. SF-6013 resulted in the discovery of a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (1), together with four known analogues, tanzawaic acids A (2) and D (3), a salt form of tanzawaic acid E (4), and tanzawaic acid B (5). Their structures were m...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2014.10.035

    authors: Quang TH,Ngan NTT,Ko W,Kim DC,Yoon CS,Sohn JH,Yim JH,Kim YC,Oh H

    更新日期:2014-12-15 00:00:00

  • Synthesis and biological evaluation of semi-synthetic albocycline analogs.

    abstract::Albocycline (ALB) is a unique macrolactone natural product with potent, narrow-spectrum activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate (VISA), and vancomycin-resistant S. aureus (VRSA) strains (MIC = 0.5-1.0 μg/mL). Described herein is the synthesis and evaluation of a nov...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2020.127509

    authors: Daher SS,Franklin KP,Scherzi T,Dunman PM,Andrade RB

    更新日期:2020-11-01 00:00:00

  • Synthesis of novel multivalent fluorescent inhibitors with high affinity to prostate cancer and their biological evaluation.

    abstract::Prostate-specific membrane antigen (PSMA) is an important biological target for therapy and diagnosis of prostate cancer. In this study, novel multivalent PSMA inhibitors with glutamate-urea-lysine structures were designed to improve inhibition characteristics. Precursors of the novel inhibitors were prepared from glu...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2018.01.047

    authors: Kwon YD,Chung HJ,Lee SJ,Lee SH,Jeong BH,Kim HK

    更新日期:2018-02-15 00:00:00

  • Chemical synthesis of S-ribosyl-L-homocysteine and activity assay as a LuxS substrate.

    abstract::Bacterial quorum sensing is mediated by autoinducers, small signaling molecules generated by bacteria. It has been proposed that the LuxS enzyme converts S-ribosyl-L-homocysteine to 4,5-dihydroxy-2,3-pentanedione, the precursor of autoinducer 2 (AI-2). We report here a chemical synthesis of S-ribosyl-L-homocysteine an...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2003.09.015

    authors: Zhao G,Wan W,Mansouri S,Alfaro JF,Bassler BL,Cornell KA,Zhou ZS

    更新日期:2003-11-17 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

  • PSMA-targeted bispecific Fab conjugates that engage T cells.

    abstract::Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.09.065

    authors: Patterson JT,Isaacson J,Kerwin L,Atassi G,Duggal R,Bresson D,Zhu T,Zhou H,Fu Y,Kaufmann GF

    更新日期:2017-12-15 00:00:00

  • 3D-QSAR studies on thieno[3,2-d]pyrimidines as phosphodiesterase IV inhibitors.

    abstract::Cyclic nucleotide phosphodiesterase IV (PDE IV) inhibitors find utility in asthma and Chronic Obstructive Pulmonary Disease (COPD) therapy. A series of 29 thieno[3,2-d]pyrimidines with affinity for PDE IV was subjected to three dimensional quantitative structure activity relationship (3D-QSAR) studies using comparativ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(03)00172-0

    authors: Chakraborti AK,Gopalakrishnan B,Sobhia ME,Malde A

    更新日期:2003-04-17 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

    doi:10.1016/j.bmcl.2012.10.090

    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

  • Binding modes of 6,7 di-substituted 4-anilinoquinoline-3-carbonitriles to EGFR.

    abstract::4-Anilino-3-cyanoquinolines were reported to have irreversible binding to epidermal growth factor receptor kinase (EGFRK) by forming a covalent linkage to C773. Our initial docking studies gave results inconsistent with the in vitro data and showed two different binding modes. To perceive the exact mode of binding of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.04.080

    authors: Akula N,Bhalla J,Sridhar J,Pattabiraman N

    更新日期:2004-07-05 00:00:00

  • Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354.

    abstract::Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was fou...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2014.08.021

    authors: Wen W,Young SE,Duvernay MT,Schulte ML,Nance KD,Melancon BJ,Engers J,Locuson CW 2nd,Wood MR,Daniels JS,Wu W,Lindsley CW,Hamm HE,Stauffer SR

    更新日期:2014-10-01 00:00:00

  • Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I.

    abstract::Herein we report 6-ethoxy-6-oxo-5-(2-phenylhydrazono) hexanoic acid and 3-(2-carboxyethyl)-1H-indole-2-carboxylic acid derivatives as synthetically accessible leads for human kynurenine aminotransferase-I (KAT-I) inhibitors. In total, 12 compounds were synthesized and their biological activities were determined using ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.12.138

    authors: Akladios FN,Nadvi NA,Park J,Hanrahan JR,Kapoor V,Gorrell MD,Church WB

    更新日期:2012-02-15 00:00:00

  • Discovery and biological evaluation of adamantyl amide 11beta-HSD1 inhibitors.

    abstract::A series of adamantyl amide 11beta-HSD1 inhibitors has been discovered and chemically modified. Selected compounds are selective for 11beta-HSD1 over 11beta-HSD2 and possess excellent cellular potency in human and murine 11beta-HSD1 assays. Good pharmacodynamic characteristics are observed in ex vivo assays. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.02.057

    authors: Webster SP,Ward P,Binnie M,Craigie E,McConnell KM,Sooy K,Vinter A,Seckl JR,Walker BR

    更新日期:2007-05-15 00:00:00

  • Novel trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines as mu opioid receptor antagonists with improved opioid receptor selectivity profiles.

    abstract::A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, mu opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective mu opioid receptor antagonist, which interacts selectively with mu peripheral recept...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.01.106

    authors: Le Bourdonnec B,Barker WM,Belanger S,Wiant DD,Conway-James NC,Cassel JA,O'Neill TJ,Little PJ,DeHaven RN,DeHaven-Hudkins DL,Dolle RE

    更新日期:2008-03-15 00:00:00

  • Optimization of anti-proliferative activity using a screening approach with a series of bis-heterocyclic G-quadruplex ligands.

    abstract::Using a phenotypic screening and SAR optimization approach, a phenyl-bis-oxazole derivative has been identified with anti-proliferative activity, optimized with the use of a panel of cancer cell lines. The lead compound was synthesized by means of a short and effective two-step synthesis using Pd-catalyzed direct aryl...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.07.057

    authors: Ohnmacht SA,Ciancimino C,Vignaroli G,Gunaratnam M,Neidle S

    更新日期:2013-10-01 00:00:00

  • Design and synthesis of 2-phenylpyrimidine coumarin derivatives as anticancer agents.

    abstract::A series of 2-phenylpyrimidine coumarin derivatives with potential telomerase-inhibiting activity was designed and synthesized. All of the compounds were screened for antiproliferative activity against CNE2, KB, and Cal27 cell lines in vitro. The results showed that most of the derivatives had a favorable effect on re...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.08.044

    authors: Lv N,Sun M,Liu C,Li J

    更新日期:2017-10-01 00:00:00

  • 2,2-Dimethyl-4,5-diaryl-3(2H)furanone derivatives as selective cyclo-oxygenase-2 inhibitors.

    abstract::A series of 2,2-dimethyl-5-[4-(methylsulfonyl)phenyl]-4-phenyl-3(2H)furanones was prepared and evaluated for their ability to inhibit cyclo-oxygenase-2 (COX-2). ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(00)00634-x

    authors: Shin SS,Noh MS,Byun YJ,Choi JK,Kim JY,Lim KM,Ha JY,Kim JK,Lee CH,Chung S

    更新日期:2001-01-22 00:00:00

  • Urokinase-type plasminogen activator expression and Rac1/WAVE-2/Arp2/3 pathway are blocked by pterostilbene to suppress cell migration and invasion in MDA-MB-231 cells.

    abstract::Breast cancer is the most common malignancy among females, and cancer invasion and metastasis are the leading causes of cancer death in breast cancer patients. Pterostilbene, a naturally occurring dimethylether analogue of resveratrol, has been demonstrated to possess anti-cancer effects. However, inhibitory effects o...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.12.115

    authors: Ko HS,Kim JS,Cho SM,Lee HJ,Ahn KS,Kim SH,Lee EO

    更新日期:2014-02-15 00:00:00

  • Synthesis and biological evaluation of nitric oxide-releasing derivatives of oleanolic acid as inhibitors of HepG2 cell apoptosis.

    abstract::A total of 106 nitric oxide-releasing derivatives of oleanolic acid were synthesized and their effects on the inhibition of anti-Fas-mediated HepG2 cell apoptosis were evaluated in vitro. Several compounds inhibited anti-Fas-mediated HepG2 cell apoptosis in a dose-dependent manner. Within this series of compounds, 8b ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.03.068

    authors: Chen L,Zhang Y,Kong X,Peng S,Tian J

    更新日期:2007-06-01 00:00:00

  • Synthesis and pharmacological evaluation of N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide as cyclooxygenase inhibitors.

    abstract::A series of novel N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide derivatives were synthesized via converting the readily available 4-hydroxy coumarin to the corresponding ethyl 2-(2-oxo-2H-chromen-4-yloxy)propanoate followed by hydrolysis and then reacting with different substituted amines. The molecular struct...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2012.08.082

    authors: Rambabu D,Mulakayala N,Ismail,Kumar KR,Kumar GP,Mulakayala C,Kumar CS,Kalle AM,Rao MV,Oruganti S,Pal M

    更新日期:2012-11-01 00:00:00

  • Design and synthesis of positional isomers of 5 and 6-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles as possible antimicrobial and antitubercular agents.

    abstract::In this Letter, we report the structure-activity relationship (SAR) studies on series of positional isomers of 5(6)-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles derivatives 7(a-j) and 8(a-j) synthesized in good yields and characterized by (1)H NMR, (13)C NMR and mass spectral analyses. The c...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.06.072

    authors: Ranjith PK,Rajeesh P,Haridas KR,Susanta NK,Row TN,Rishikesan R,Kumari NS

    更新日期:2013-09-15 00:00:00

  • Biological properties of synthetic glycoconjugate mimics of heparin comprising different molecular spacers.

    abstract::The in vitro antithrombotic activity of synthetic glycoconjugates I and II, comprising a flexible polyethylene glycol type and a rigid polyglucose type spacer, respectively, are compared to heparin. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(98)00382-5

    authors: Dreef-Tromp CM,Basten JE,Broekhoven MA,van Dinther TG,Petitou M,van Boeckel CA

    更新日期:1998-08-18 00:00:00