Structure-activity relationship studies of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of HCV NS3 serine protease.

Abstract:

:A survey of isosteric replacements of the phosphonoalanine side chain coupled with a process of conformational constraint of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease resulted in the identification of novel series of active compounds with extended side chains. However, Zn(2+)-dependent HCV NS3 inhibition was relatively insensitive to the structural variations examined but dependent on the presence of negatively charged functionality. This result was interpreted in the context of an initial electrostatic interaction between protease and inhibitor that is subsequently consolidated by Zn(2+), with binding facilitated by the featureless active site and proximal regions of the HCV NS3 protein.

journal_name

Bioorg Med Chem Lett

authors

Yeung KS,Meanwell NA,Qiu Z,Hernandez D,Zhang S,McPhee F,Weinheimer S,Clark JM,Janc JW

doi

10.1016/s0960-894x(01)00457-7

subject

Has Abstract

pub_date

2001-09-03 00:00:00

pages

2355-9

issue

17

eissn

0960-894X

issn

1464-3405

pii

S0960894X01004577

journal_volume

11

pub_type

杂志文章
  • Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide.

    abstract::Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activit...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.05.099

    authors: Robinson RP,Bartlett JA,Bertinato P,Bessire AJ,Cosgrove J,Foley PM,Manion TB,Minich ML,Ramos B,Reese MR,Schmahai TJ,Swick AG,Tess DA,Vaz A,Wolford A

    更新日期:2011-07-15 00:00:00

  • Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 5.

    abstract::A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.11.007

    authors: Takeuchi K,Kohn TJ,Honigschmidt NA,Rocco VP,Spinazze PG,Hemrick-Luecke SK,Thompson LK,Evans DC,Rasmussen K,Koger D,Lodge D,Martin LJ,Shaw J,Threlkeld PG,Wong DT

    更新日期:2006-05-01 00:00:00

  • Synthesis and evaluation of novel phosphoramidate prodrugs of 2'-methyl cytidine as inhibitors of hepatitis C virus NS5B polymerase.

    abstract::A variety of new prodrugs of 2'-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieve...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.01.035

    authors: Donghi M,Attenni B,Gardelli C,Marco AD,Fiore F,Giuliano C,Laufer R,Leone JF,Pucci V,Rowley M,Narjes F

    更新日期:2009-03-01 00:00:00

  • Nonpeptide oxytocin antagonists: potent, orally bioavailable analogs of L-371,257 containing a 1-R-(pyridyl)ethyl ether terminus.

    abstract::Structure-activity studies on the oxytocin antagonist 1 (L-371,257) have identified a new series of high affinity, receptor-selective OT antagonists in which the N-acetyl-4-piperidinyl ether terminus in 1 has been replaced with a 1-(aryl)ethoxy group. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/S0960-894X(98)00568-X

    authors: Kuo MS,Bock MG,Freidinger RM,Guidotti MT,Lis EV,Pawluczyk JM,Perlow DS,Pettibone DJ,Quigley AG,Reiss DR,Williams PD,Woyden CJ

    更新日期:1998-11-03 00:00:00

  • The synthesis of xanthones, xanthenediones, and spirobenzofurans: their antibacterial and antifungal activity.

    abstract::Exposure of the phenol, (5-bromo-2-hydroxyphenyl)(2,4,5-trimethoxyphenyl)methanone 18 to ceric ammonium nitrate (CAN) resulted in the formation of 7-bromo-3,4a-dimethoxy-2H-xanthene-2,9(4aH)-dione 19 and 5-bromo-2',5'-dimethoxy-3H-spiro[benzofuran-2,1'-cyclohexa[2,5]diene]-3,4'-dione 20. The brominated spirobenzofuran...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.09.088

    authors: Omolo JJ,Johnson MM,van Vuuren SF,de Koning CB

    更新日期:2011-12-01 00:00:00

  • Advances in Lead Generation.

    abstract::Lead Generation represents a critical drug discovery phase where chemical starting points and their respective mechanism of action, quality, and potential liabilities are largely predefined. Recent advances such as DNA-encoded libraries or fragment-, chemical biology-, and virtual screening-based approaches are today ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.bmcl.2018.12.001

    authors: Holenz J,Stoy P

    更新日期:2019-02-15 00:00:00

  • Solvent free, catalyst free, microwave or grinding assisted synthesis of bis-cyclic imide derivatives and their evaluation for anticancer activity.

    abstract::Cyclic imides are well known to be very important antitumor agents such as mitonafide and amonafide etc. Based on this fact, we have synthesized two series of cyclic imide derivatives containing two cyclic imide moiety in their structures (bis-cyclic imides) and screened them for in vitro anticancer activity against f...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.12.031

    authors: Kumar A,Banerjee S,Roy P,Sondhi SM,Sharma A

    更新日期:2017-02-01 00:00:00

  • 6-Alkoxyisoindolin-1-one based dopamine D2 partial agonists as potential antipsychotics.

    abstract::A series of 6-alkoxyisoindolin-1-ones with a magic shotgun pharmacological profile are presented as potential antipsychotics. The in vitro pharmacological profile includes D(2) partial agonism (30-55%), 5-HT(1A) partial agonism (60-90%), and 5-HT(2A) antagonism. Selected compounds in this series displayed good in vivo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.08.023

    authors: Favor DA,Powers JJ,White AD,Fitzgerald LW,Groppi V,Serpa KA

    更新日期:2010-10-01 00:00:00

  • Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas.

    abstract::We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.05.097

    authors: Hart T,Macias AT,Benwell K,Brooks T,D'Alessandro J,Dokurno P,Francis G,Gibbons B,Haymes T,Kennett G,Lightowler S,Mansell H,Matassova N,Misra A,Padfield A,Parsons R,Pratt R,Robertson A,Walls S,Wong M,Roughley S

    更新日期:2009-08-01 00:00:00

  • Synthesis and structure evaluation of a novel cantharimide and its cytotoxicity on SK-Hep-1 hepatoma cells.

    abstract::A remarkable control of the potency of cantharimide is described based on the electronic properties of functional group and it exhibits a relatively less toxic effect to the non-malignant hematological disorder bone marrow cells. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2006.12.039

    authors: Kok SH,Chui CH,Lam WS,Chen J,Lau FY,Wong RS,Cheng GY,Lai PB,Leung TW,Yu MW,Tang JC,Chan AS

    更新日期:2007-03-01 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

    doi:10.1016/s0960-894x(02)00922-8

    authors: Cheruvallath ZS,Cole DL,Ravikumar VT

    更新日期:2003-01-20 00:00:00

  • Design, synthesis and biological study of pinacolyl boronate-substituted stilbenes as novel lipogenic inhibitors.

    abstract::A pilot library of novel 4,4,5,5-tetramethyl-2-(4-substitutedstyrylphenyl)-1,3,2 dioxaborolane derivatives has been synthesized. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide 3 was treated with various aldehydes in the presence of 3 equiv of (t)BuONa in DMF, and stirred at room te...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.05.124

    authors: Das BC,Zhao X,Tang XY,Yang F

    更新日期:2011-09-15 00:00:00

  • S-aryl cysteine S,S-dioxides as inhibitors of mammalian kynureninase.

    abstract::A series of 2-amino-S-aryl cysteine S,S-dioxides have been synthesised and shown to inhibit kynureninase an important enzyme in the biosynthesis of the known excitotoxic moiety quinolinic acid. The most potent of these, 2-amino-5-methyl-S-phenyl cysteine S,S-dioxide 6d, inhibits interferon-gamma induced synthesis of q...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(97)10209-8

    authors: Drysdale MJ,Reinhard JF

    更新日期:1998-01-20 00:00:00

  • Identification of optimum computational protocols for modeling the aryl hydrocarbon receptor (AHR) and its interaction with ligands.

    abstract::The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic receptors in living organisms and is responsible for interacting with several drugs and environmental toxins, most notably tetrachlorodibenzodioxin (TCDD). Binding of diverse agonists to AHR initiates an extensive set of downstream gene expression ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.09.019

    authors: Jogalekar AS,Reiling S,Vaz RJ

    更新日期:2010-11-15 00:00:00

  • Synthesis of pyrrolomorphinan derivatives as kappa opioid agonists.

    abstract::We synthesized pyrrolomorphinan derivatives 6, 7, and 9 to examine whether the pyrrole ring would be an accessory site in the kappa opioid receptor selective antagonist, nor-binaltorphimine. Derivative 6 had an alpha,beta-unsaturated ketone substituent that strongly bound to the kappa receptor. The compound with the h...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.07.035

    authors: Fujii H,Ida Y,Hanamura S,Osa Y,Nemoto T,Nakajima M,Hasebe K,Nakao K,Mochizuki H,Nagase H

    更新日期:2010-09-01 00:00:00

  • Potent and selective alpha1A adrenoceptor partial agonists--novel imidazole frameworks.

    abstract::Novel imidazole frameworks have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor sub-types. Nitrile 28 possessed attractive CNS drug-like properties with good membrane permeability and no P-pg mediated efflux. 28...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.03.162

    authors: Whitlock GA,Brennan PE,Roberts LR,Stobie A

    更新日期:2009-06-01 00:00:00

  • An additional 2'-ribofuranose residue at a specific position of the DNA primer prevents Its elongation by HIV-1 reverse transcriptase.

    abstract::Oligodeoxynucleotides containing 2'-O-beta-D-ribofuranosyladenosine were prepared and used as modified primers in RNA-templated DNA synthesis catalyzed by HIV reverse transcriptase. It was shown that the additional 2'-ribofuranose residue in specific position of primer prevents its elongation. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(01)00836-8

    authors: Andreeva OI,Golubeva AS,Kochetkov SN,Van Aerschot A,Herdewijn P,Efimtseva EV,Ermolinsky BS,Mikhailov SN

    更新日期:2002-02-25 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

  • Preliminary in vivo evaluation of a novel 99mTc-labeled HYNIC-cys-annexin A5 as an apoptosis imaging agent.

    abstract::A novel cys-annexin A5 with a single cysteine-residue at its concave side has been developed by site-directed mutagenesis to allow conjugation through thiol-chemistry without affecting its apoptotic cell binding properties and was derivatized with HYNIC in a 1:1 stoichiometry. Similar to that of the 1st generation 99m...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.05.044

    authors: Fonge H,de Saint Hubert M,Vunckx K,Rattat D,Nuyts J,Bormans G,Ni Y,Reutelingsperger C,Verbruggen A

    更新日期:2008-07-01 00:00:00

  • Antitumor activity of tetrahydroisoquinoline analogues 3-epi-jorumycin and 3-epi-renieramycin G.

    abstract::Analogues of the tetrahydroisoquinoline family of antitumor antibiotics, 3-epi-jorumycin (3) and 3-epi-renieramycin G (4), in addition to their respective parent natural products (-)-jorumycin (1) and (-)-renieramycin G (2) were evaluated against both human colon (HCT-116) and human lung (A549) cancer cell lines. (-)-...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2006.03.042

    authors: Lane JW,Estevez A,Mortara K,Callan O,Spencer JR,Williams RM

    更新日期:2006-06-15 00:00:00

  • Identification of peptidomimetic HTLV-I protease inhibitors containing hydroxymethylcarbonyl (HMC) isostere as the transition-state mimic.

    abstract::Towards the development of chemotherapy for the infection by human T-cell leukemia virus type I (HTLV-I), we have established evaluation systems for HTLV-I protease (PR) inhibitors using both recombinant and chemically synthesized HTLV-I PRs. Newly synthesized substrate-based inhibitors containing hydroxymethylcarbony...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.09.034

    authors: Maegawa H,Kimura T,Arii Y,Matsui Y,Kasai S,Hayashi Y,Kiso Y

    更新日期:2004-12-06 00:00:00

  • Piperidine-based renin inhibitors: upper chain optimization.

    abstract::The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.08.087

    authors: Corminboeuf O,Bezençon O,Remeň L,Grisostomi C,Richard-Bildstein S,Bur D,Prade L,Strickner P,Hess P,Fischli W,Steiner B,Treiber A

    更新日期:2010-11-01 00:00:00

  • Design and efficient synthesis of new stable 1alpha,25-dihydroxy-19-norvitamin D3 analogues containing amide bond.

    abstract::The design and synthesis of new 1alpha,25-dihydroxy-19-norvitamin D(3) analogues 3a-c, which have an amide bond in the molecule instead of the diene, are described. The A-ring moiety was constructed by a (3S,5S)-3,5-dihydroxypiperidine derivative (9, 11, or 13) prepared from D-mannose, and a CD-ring carboxylic acid 16...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(02)00800-4

    authors: Suhara Y,Kittaka A,Ono K,Kurihara M,Fujishima T,Yoshida A,Takayama H

    更新日期:2002-12-16 00:00:00

  • Stereoselective synthesis of 15- and 16-substituted isosteviol derivatives and their cytotoxic activities.

    abstract::By means of functional interconversions in ring D of the tetracyclic diterpene isosteviol (ent-16-ketobeyeran-19-oic acid 1), various 15- and 16-substituted isosteviol derivatives were stereoselectively prepared. The cytotoxic activities in vitro of these new isosteviol derivatives were investigated, and some of them ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.12.101

    authors: Wu Y,Dai GF,Yang JH,Zhang YX,Zhu Y,Tao JC

    更新日期:2009-03-15 00:00:00

  • Powerful probes for glycosidases: novel, fluorescently tagged glycosidase inhibitors.

    abstract::Amino-1,2,5-trideoxy-2,5-imino-D-mannitol was fluorescently tagged by reaction with dansyl chloride at N-1 or by attachment of a dansyl amide bearing spacer to this centre. Compounds obtained are highly potent inhibitors of beta-glucosidase exhibiting Ki values in the single figure nanomolar range. The 1-N-dansyl subs...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(01)00209-8

    authors: Hermetter A,Scholze H,Stütz AE,Withers SG,Wrodnigg TM

    更新日期:2001-05-21 00:00:00

  • The discovery of potent antagonists of NPBWR1 (GPR7).

    abstract::The synthesis and evaluation of small molecule antagonists of the G protein-coupled receptor NPBWR1 (GPR7) are reported for the first time. [4-(5-Chloropyridin-2-yl)piperazin-1-yl][(1S,2S,4R)-4-{[(1R)-1-(4-methoxyphenyl)ethyl]amino}-2-(thiophen-3-yl)cyclohexyl]methanone (1) emerged as a hit from a high-throughput scre...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.11.126

    authors: Anthony Romero F,Hastings NB,Moningka R,Guo Z,Wang M,Di Salvo J,Lei Y,Trusca D,Deng Q,Tong V,Terebetski JL,Ball RG,Ujjainwalla F

    更新日期:2012-01-15 00:00:00

  • New nemadectin congeners with acaricidal and nematocidal activity from Streptomyces microflavus neau3 Y-3.

    abstract::Two nemadectin congeners 1 and 2 were isolated from the fermentation broth of a mutant strain (Y-3) of Streptomyces microflavus neau3. Their structures were determined on the basis of extensive spectroscopic analysis and comparison with data from the literature. Compound 2 possessed a 5-membered ring lactone that is u...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.08.002

    authors: Yang LY,Wang JD,Zhang J,Xue CY,Zhang H,Wang XJ,Xiang WS

    更新日期:2013-10-15 00:00:00

  • PET imaging and optical imaging with D-luciferin [11C]methyl ester and D-luciferin [11C]methyl ether of luciferase gene expression in tumor xenografts of living mice.

    abstract::New carbon-11 labeled D-luciferin analogs D-luciferin [(11)C]methyl ester ([(11)C]LMEster, [(11)C]1) and D-luciferin [(11)C]methyl ether ([(11)C]LMEther, [(11)C]2) were synthesized in 25-55% radiochemical yield. PET studies with [(11)C]LMEster and [(11)C]LMEther demonstrate a lower retention of the C-11 label at 45 mi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.09.082

    authors: Wang JQ,Pollok KE,Cai S,Stantz KM,Hutchins GD,Zheng QH

    更新日期:2006-01-15 00:00:00

  • Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors.

    abstract::A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excell...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.03.026

    authors: Sabat M,Wang H,Scorah N,Lawson JD,Atienza J,Kamran R,Hixon MS,Dougan DR

    更新日期:2017-05-01 00:00:00

  • Synthesis and cytotoxicity of (-)-renieramycin G analogs.

    abstract::(-)-Renieramycin G and fifteen C-22 analogs were prepared employing l-tyrosine as the chiral starting material. These analogs, along with (-)-renieramycin G itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, A2780, MCF-7, A549, BGC-823, Ketr3, KB, Hela cells. The IC(50) values of most of these a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.01.025

    authors: Liu W,Dong W,Liao X,Yan Z,Guan B,Wang N,Liu Z

    更新日期:2011-03-01 00:00:00