Synthesis and SAR of acyclic HCV NS3 protease inhibitors with novel P4-benzoxaborole moieties.


:We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.


Bioorg Med Chem Lett


Li X,Zhang S,Zhang YK,Liu Y,Ding CZ,Zhou Y,Plattner JJ,Baker SJ,Bu W,Liu L,Kazmierski WM,Duan M,Grimes RM,Wright LL,Smith GK,Jarvest RL,Ji JJ,Cooper JP,Tallant MD,Crosby RM,Creech K,Ni ZJ,Zou W,Wright J




Has Abstract


2011-04-01 00:00:00














  • Enantioselective biocatalytic synthesis of (S)-monastrol.

    abstract::The first enantioselective biocatalytic synthesis of (S)-monastrol has been developed via an unexpected and unusual enzymatic pathway as suitable route. Whereas attempts for a direct hydrolysis of racemic monastrol were not successful, formation of racemic O-butanoyl monastrol and subsequent enantioselective hydrolysi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Blasco MA,Thumann S,Wittmann J,Giannis A,Gröger H

    更新日期:2010-08-01 00:00:00

  • Parallel synthesis of acylsemicarbazide libraries: preparation of potent cyclin dependent kinase (cdk) inhibitors.

    abstract::Potent cyclin dependent kinase inhibitors were prepared using parallel synthesis methodology. Treating advanced intermediate 2 with a variety of hydrazides in DMSO at 80 degrees C for 30 min gave the desired acylsemicarbazides in good to excellent yield. Several compounds were active against cdk4/D1 and cdk2/E in the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nugiel DA,Vidwans A,Dzierba CD

    更新日期:2004-11-15 00:00:00

  • Enzyme inhibition potency enhancement by active site metal chelating and hydrogen bonding induced conformation-restricted cyclopropanecarbonyl derivatives.

    abstract::Two cyclopropanecarbonyl derivatives were independently found to be 15 and 14 times more potent than the corresponding isopropylcarbonyl analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase and dihydroorotate dehydrogenase, respectively. A thorough examination of the co-crystal structures of available enzyme...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kuo PY,Shie TL,Chen YS,Lai JT,Yang DY

    更新日期:2006-12-01 00:00:00

  • Intramolecular aldol cyclization of L-lyxo-hexos-5-ulose derivatives: a new diastereoselective synthesis of D-chiro-inositol.

    abstract::The DBU-promoted intramolecular aldol condensation of two partially protected L-lyxo-hexos-5-ulose derivatives (8 and 9), in turn obtained starting from methyl beta-D-galactopyranoside, takes place with fairly good yield and complete diastereoselectivity to give 2L-(2,3,6/4,5)-pentahydroxycyclohexanone derivatives, 10...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Catelani G,Corsaro A,D'Andrea F,Mariani M,Pistarà V

    更新日期:2002-11-18 00:00:00

  • Heterocyclic sulfoxide and sulfone inhibitors of fatty acid amide hydrolase.

    abstract::A novel series of heterocyclic sulfoxides and sulfones was prepared and examined as potential inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for inactivation of neuromodulating fatty acid amides including anandamide and oleamide. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Du W,Hardouin C,Cheng H,Hwang I,Boger DL

    更新日期:2005-01-03 00:00:00

  • Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity.

    abstract::The concurrent implementation of a proteome-wide serine hydrolase selectivity screen with traditional efforts to optimize fatty acid amide hydrolase (FAAH) inhibition potency led to the expedited discovery of a new class of exceptionally potent (Ki < 300 pM) and unusually selective (> 100-fold selective) inhibitors. T...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Leung D,Du W,Hardouin C,Cheng H,Hwang I,Cravatt BF,Boger DL

    更新日期:2005-03-01 00:00:00

  • Discovery of a novel series of selective HCN1 blockers.

    abstract::The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubsti...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: McClure KJ,Maher M,Wu N,Chaplan SR,Eckert WA 3rd,Lee DH,Wickenden AD,Hermann M,Allison B,Hawryluk N,Breitenbucher JG,Grice CA

    更新日期:2011-09-15 00:00:00

  • Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma.

    abstract::A number of compounds bearing a quaternary ammonium moiety were found to be antagonists with nanomolar binding affinity for the chemokine receptor-2. The structure-activity relationships in the series are described herein along with some detailed characterization of the interesting compounds. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lagu B,Gerchak C,Pan M,Hou C,Singer M,Malaviya R,Matheis M,Olini G,Cavender D,Wachter M

    更新日期:2007-08-01 00:00:00

  • Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity.

    abstract::Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice. suggesting that 5k ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hanano T,Adachi K,Aoki Y,Morimoto H,Naka Y,Hisadome M,Fukuda T,Sumichika H

    更新日期:2000-05-01 00:00:00

  • Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors.

    abstract::Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator in insulin- and leptin-signaling cascades as well as a positive regulator in tumorigenesis, and much attention has been paid to PTP1B inhibitors as potential therapies for diabetes, obesity, and cancer. In the present study, the screening of a compo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li W,Li S,Higai K,Sasaki T,Asada Y,Ohshima S,Koike K

    更新日期:2013-11-01 00:00:00

  • Imidazolopyrazinones as potential antioxidants.

    abstract::A series of imidazolopyrazinones 3, substituted at C-2, and C-2/C-6, has been prepared. The compounds behaved as quenchers of superoxide anion. The more active compounds are structurally related to coelenterazine, a natural substrate of marine bioluminescence. Theoretical parameters based on Hartree-Fock instabilities...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Devillers I,Dive G,De Tollenaere C,Falmagne B,de Wergifosse B,Rees JF,Marchand-Brynaert J

    更新日期:2001-09-03 00:00:00

  • Synthesis, antimycobacterial and antibacterial activity of ciprofloxacin derivatives containing a N-substituted benzyl moiety.

    abstract::We report herein the design and synthesis of a series of novel ciprofloxacin (CPFX) derivatives with remarkable improvement in lipophilicity by introducing a substituted benzyl moiety to the N atom on the C-7 piperazine ring of CPFX. Antimycobacterial and antibacterial activity of the newly synthesized compounds was e...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang S,Jia XD,Liu ML,Lu Y,Guo HY

    更新日期:2012-09-15 00:00:00

  • Discovery of core-structurally novel PTP1B inhibitors with specific selectivity containing oxindole-fused spirotetrahydrofurochroman by one-pot reaction.

    abstract::Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an ideal target for treatment of type II diabetes and obesity. However, no druggable PTP1B inhibitor has been established and there is still an urgent demand for the development of structurally novel PTPIB inhibitor. Herein, we reported core-structurally ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dong S,Lei Y,Jia S,Gao L,Li J,Zhu T,Liu S,Hu W

    更新日期:2017-02-15 00:00:00

  • Cyclopenta[g]quinazoline-based antifolates: the effect of the chirality at the 6-position on the inhibition of thymidylate synthase (TS).

    abstract::Cyclopenta[g]quinazoline-based inhibitors of thymidylate synthase (TS) possess a chiral centre at the 6-position of the molecule. The effect of this chirality on the inhibition of TS was investigated by synthesising compounds 6S-1a-c, 6R-1a-c. It was shown, in particular with the diastereoisomers 6S-1c, 6R-1c, that th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bavetsias V,Marriott JH,Theti DS,Melin JC,Wilson SC,Jackman AL

    更新日期:2001-12-03 00:00:00

  • 5-Alkyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-ones as potent non-nucleoside reverse transcriptase inhibitors of S-DABO series.

    abstract::Novel dihydroalkoxybenzyloxopyrimidine (S-DABO) derivatives targeting the non-nucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been synthesized using a novel computer model for the NNI binding pocket and tested for their RT inhibitory activity in cell-free a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Vig R,Mao C,Venkatachalam TK,Tuel-Ahlgren L,Sudbeck EA,Uckun FM

    更新日期:1998-06-16 00:00:00

  • Design and regioselective synthesis of a new generation of targeted chemotherapeutics. Part II: Folic acid conjugates of tubulysins and their hydrazides.

    abstract::Efficient syntheses of folate conjugates of tubulysins and their hydrazides 1a-d are described. These water soluble folate receptor (FR) targeted conjugates are derivatives of folic acid and the potent cytotoxic agents: tubulysin A, B, or their respective hydrazides, connected in regioselective manner via a hydrophili...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Vlahov IR,Wang Y,Kleindl PJ,Leamon CP

    更新日期:2008-08-15 00:00:00

  • Insights into the substrate specificity of the MutT pyrophosphohydrolase using structural analogues of 8-oxo-2'-deoxyguanosine nucleotide.

    abstract::The bacterial repair enzyme MutT hydrolyzes the damaged nucleotide OdGTP (the 5'-triphosphate derivative of 8-oxo-2'-deoxyguanosine; OdG), which is a known mutagen and has been linked to antibacterial action. Previous work has indicated important roles for the C8-oxygen, N7-hydrogen, and C2-exocyclic amine during OdGT...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hamm ML,McFadden EJ,Ghio M,Lindell MA,Gerien KS,O'Handley SF

    更新日期:2016-04-15 00:00:00

  • Discovery of 5-substituted-N-arylpyridazinones as inhibitors of p38 MAP kinase.

    abstract::The synthesis, structure-activity relationship and modeling of a series of 5-substituted-N-aryl pyridazinone based p38alpha inhibitors are described. In comparing the series to the similar N-aryl pyridinone series, it was found that the pyridazinones maintained a weaker interaction to the p38 enzyme, and therefore sho...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Jerome KD,Hepperle ME,Walker JK,Xing L,Devraj RV,Benson AG,Baldus JE,Selness SR

    更新日期:2010-05-15 00:00:00

  • Synthesis and antifungal activity of the 2,2,5-tetrahydrofuran regioisomers of SCH 51048.

    abstract::The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lovey RG,Saksena AK,Girijavallabhan VM,Blundell P,Guzik H,Loebenberg D,Parmegiani RM,Cacciapuoti A

    更新日期:2002-07-08 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

  • Synthesis of 4'-modified noraristeromycins to clarify the effect of the 4'-hydroxyl groups for inhibitory activity against S-adenosyl-L-homocysteine hydrolase.

    abstract::4'-Modified noraristeromycin (NAM) analogs, 4'-sulfo-, 4'-sulfamoy, 4'-azido and 4'-amino-NAM, were systematically synthesized. The inhibitory activities of these analogs and related compounds against Plasmodium falciparum and human S-adenosyl-L-homocysteine hydrolase were investigated. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ando T,Kojima K,Chahota P,Kozaki A,Milind ND,Kitade Y

    更新日期:2008-04-15 00:00:00

  • Synthesis of a Streptococcus pyogenes vaccine candidate based on the M protein PL1 epitope.

    abstract::Group A streptococcus is a Gram-positive bacteria that causes a range of infectious diseases. Targeting the bacteria, a new self-adjuvanting vaccine candidate, incorporating a carbohydrate carrier and an amino acid-based adjuvant, was synthesised utilising carbohydrate chemistry and solid-phase peptide synthesis proce...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Simerska P,Lu H,Toth I

    更新日期:2009-02-01 00:00:00

  • Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols.

    abstract::A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kim CY,Mahaney PE,McConnell O,Zhang Y,Manas E,Ho DM,Deecher DC,Trybulski EJ

    更新日期:2009-09-01 00:00:00

  • Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines.

    abstract::A series of 1-isoquinolinylguanidines are shown to be potent inhibitors of uPA with selectivity over tPA and plasmin. Potency is enhanced by the presence of a 4-halo and a 7-aryl substituent, particularly when substituted by a 3-carboxylic acid group. Compound 13j (UK-356,202) combines excellent potency and selectivit...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Barber CG,Dickinson RP,Fish PV

    更新日期:2004-06-21 00:00:00

  • (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives as high affinity h5-HT1B/1D ligands.

    abstract::A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Egle I,MacLean N,Demchyshyn L,Edwards L,Slassi A,Tehim A

    更新日期:2003-10-20 00:00:00

  • N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists.

    abstract::Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimizati...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wu L,Lu K,Desai M,Packiarajan M,Joshi A,Marzabadi MR,Jubian V,Andersen K,Chandrasena G,Boyle NJ,Walker MW

    更新日期:2011-09-15 00:00:00

  • Potential hypotensive agents: synthesis and hypotensive activity of oxime ethers derived from 1-naphthoxepines and related compounds.

    abstract::The synthesis and pharmacological evaluation of substituted oximino-ethers 1 and 2 of naphth[1,2-b]- and naphth[2,1-b]-oxepin-5-ones (4 and 8) were carried out. The hypotensive activity of oximino-ethers 1 and 2 was evaluated on anaesthetized cats. The results indicated that 1c caused a fall of 80 mm/Hg for >100' at a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tandon VK,Kumar M,Awasthi AK,Saxena HO,Goswamy GK

    更新日期:2004-06-21 00:00:00

  • Cyclonatsudamine A, a new vasodilator cyclic peptide from Citrus natsudaidai.

    abstract::A new cyclic heptapeptide, cyclonatsudamine A (1), cyclo (-Gly-Tyr-Leu-Leu-Pro-Pro-Ser-), has been isolated from the peels of Citrus natsudaidai and the structure was elucidated by 2D NMR analysis and chemical degradation. Cyclonatsudamine A (1) relaxed norepinephrine-induced contractions of rat aorta, which may be me...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Morita H,Enomoto M,Hirasawa Y,Iizuka T,Ogawa K,Kawahara N,Goda Y,Matsumoto T,Takeya K

    更新日期:2007-10-01 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


    authors: Holenz J,Stoy P

    更新日期:2019-02-15 00:00:00

  • A graftable LDV peptidomimetic: design, synthesis and application to a blood filtration membrane.

    abstract::A graftable LDV (Leu-Asp-Val) peptidomimetic molecule (B-c) has been prepared from 3-(5-amino-2-hydroxy)phenyl-propionic acid, as alpha(4)beta(1) (VLA-4) integrin ligand. For that purpose, the mechanism of 3-(4-azidophenyl)propionic acid rearrangement has been revisited. Activation of Durapore DVPP-hydrophilic membran...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Momtaz M,Rerat V,Gharbi S,Gérard E,Pourcelle V,Marchand-Brynaert J

    更新日期:2008-02-01 00:00:00