Publications by authors named "Richard L Jarvest"

17 Publications

  • Page 1 of 1

Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.

Bioorg Med Chem Lett 2012 Dec 22;22(24):7351-6. Epub 2012 Oct 22.

Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.

We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
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http://dx.doi.org/10.1016/j.bmcl.2012.10.075DOI Listing
December 2012

Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.

J Med Chem 2012 Apr 3;55(7):3021-6. Epub 2012 Apr 3.

GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA.

The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
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http://dx.doi.org/10.1021/jm201278qDOI Listing
April 2012

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

Bioorg Med Chem Lett 2011 Apr 23;21(7):2048-54. Epub 2011 Feb 23.

Anacor Pharmaceuticals, Inc, 1020 E Meadow Circle, Palo Alto, CA 94303, USA.

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.
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http://dx.doi.org/10.1016/j.bmcl.2011.02.006DOI Listing
April 2011

Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease.

Bioorg Med Chem Lett 2010 Dec 21;20(24):7317-22. Epub 2010 Oct 21.

Anacor Pharmaceuticals, Inc., Palo Alto, CA 94303, USA.

We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
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http://dx.doi.org/10.1016/j.bmcl.2010.10.071DOI Listing
December 2010

Synthesis of new acylsulfamoyl benzoxaboroles as potent inhibitors of HCV NS3 protease.

Bioorg Med Chem Lett 2010 Dec 30;20(24):7493-7. Epub 2010 Oct 30.

Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.

HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
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http://dx.doi.org/10.1016/j.bmcl.2010.10.007DOI Listing
December 2010

Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.

Bioorg Med Chem Lett 2010 Oct 10;20(19):5695-700. Epub 2010 Aug 10.

Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
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http://dx.doi.org/10.1016/j.bmcl.2010.08.022DOI Listing
October 2010

6-Alkylquinolone-3-carboxylic acid tethered to macrolides synthesis and antimicrobial profile.

Bioorg Med Chem 2010 Sep 3;18(17):6569-77. Epub 2010 Jul 3.

GlaxoSmithKline Research Centre Zagreb Ltd, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.

Two series of clarithromycin and azithromycin derivatives with terminal 6-alkylquinolone-3-carboxylic unit with central ether bond in the linker were prepared and tested for antimicrobial activity. Quinolone-linker intermediates were prepared by Sonogashira-type C(6)-alkynylation of 6-iodo-quinolone precursors. In the last step, 4'' site-selective acylation of 2'-protected macrolides was completed with the EDC reagent, which selectively activated a terminal, aliphatic carboxylic group in dicarboxylic intermediates. Antimicrobial activity of the new series of macrolones is discussed. The most potent compound, 4''-O-{6-[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-propoxy]-hexanoyl}-azithromycin (10), is highly active against bacterial respiratory pathogens resistant to macrolide antibiotics and represents a promising lead for further investigation.
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http://dx.doi.org/10.1016/j.bmc.2010.06.048DOI Listing
September 2010

Synthesis and evaluation of novel alpha-amino cyclic boronates as inhibitors of HCV NS3 protease.

Bioorg Med Chem Lett 2010 Jun 20;20(12):3550-6. Epub 2010 May 20.

Anacor Pharmaceuticals, Inc., Palo Alto, CA 94303, USA.

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.129DOI Listing
June 2010

Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate.

J Med Chem 2007 Mar 2;50(5):897-900. Epub 2007 Feb 2.

Infectious Diseases CEDD and Medicinal Discovery Research, GlaxoSmithKline, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.
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http://dx.doi.org/10.1021/jm061207rDOI Listing
March 2007

Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase.

Bioorg Med Chem Lett 2005 May;15(9):2305-9

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.
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http://dx.doi.org/10.1016/j.bmcl.2005.03.003DOI Listing
May 2005

Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues.

Bioorg Med Chem Lett 2004 Aug;14(15):3937-41

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
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http://dx.doi.org/10.1016/j.bmcl.2004.05.070DOI Listing
August 2004

Concise synthesis, preparative resolution, absolute configuration determination, and applications of an atropisomeric biaryl catalyst for asymmetric acylation.

J Org Chem 2003 Sep;68(19):7379-85

Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK, Pfizer Global Research and Development-LaJolla, 10777 Science Center Drive, San Diego, California 92121, USA.

A new three-step synthesis and resolution of nucleophilic catalyst 1 suitable for large-scale preparation has been developed, and this catalyst has been shown to be effective for the kinetic resolution and asymmetric desymmetrization of a range of sec-alcohol substrates.
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http://dx.doi.org/10.1021/jo034603fDOI Listing
September 2003

Variable sensitivity to bacterial methionyl-tRNA synthetase inhibitors reveals subpopulations of Streptococcus pneumoniae with two distinct methionyl-tRNA synthetase genes.

Antimicrob Agents Chemother 2003 Jun;47(6):1784-9

Department of Microbiology, Microbial, Musculoskeletal, and Proliferative Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.

As reported previously (J. R. Jarvest et al., J. Med. Chem. 45:1952-1962, 2002), potent inhibitors (at nanomolar concentrations) of Staphylococcus aureus methionyl-tRNA synthetase (MetS; encoded by metS1) have been derived from a high-throughput screening assay hit. Optimized compounds showed excellent activities against staphylococcal and enterococcal pathogens. We report on the bimodal susceptibilities of S. pneumoniae strains, a significant fraction of which was found to be resistant (MIC, > or =8 mg/liter) to these inhibitors. Using molecular genetic techniques, we have found that the mechanism of resistance is the presence of a second, distantly related MetS enzyme, MetS2, encoded by metS2. We present evidence that the metS2 gene is necessary and sufficient for resistance to MetS inhibitors. PCR analysis for the presence of metS2 among a large sample (n = 315) of S. pneumoniae isolates revealed that it is widespread geographically and chronologically, occurring at a frequency of about 46%. All isolates tested also contained the metS1 gene. Searches of public sequence databases revealed that S. pneumoniae MetS2 was most similar to MetS in Bacillus anthracis, followed by MetS in various non-gram-positive bacterial, archaeal, and eukaryotic species, with streptococcal MetS being considerably less similar. We propose that the presence of metS2 in specific strains of S. pneumoniae is the result of horizontal gene transfer which has been driven by selection for resistance to some unknown class of naturally occurring antibiotics with similarities to recently reported synthetic MetS inhibitors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC155832PMC
http://dx.doi.org/10.1128/aac.47.6.1784-1789.2003DOI Listing
June 2003

Conformational restriction of methionyl tRNA synthetase inhibitors leading to analogues with potent inhibition and excellent gram-positive antibacterial activity.

Bioorg Med Chem Lett 2003 Apr;13(7):1265-8

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK.

Conformationally restricted analogues of the central linker unit of bacterial methionyl tRNA synthetase (MRS) inhibitors have been prepared. The (1S,2R)-cyclopentylmethyl moiety was identified as the preferred cyclic linker, with significant diastereo- and enantioselectivity of activity. Combination of this linker with an optimal substituted aryl right-hand side has resulted in a compound with exceptionally good antibacterial activity against staphylococci and enterococci, including antibiotic resistant strains.
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http://dx.doi.org/10.1016/s0960-894x(03)00093-3DOI Listing
April 2003

Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity.

Bioorg Med Chem Lett 2003 Feb;13(4):665-8

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.
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http://dx.doi.org/10.1016/s0960-894x(02)01027-2DOI Listing
February 2003

The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase.

Bioorg Med Chem Lett 2002 Nov;12(21):3171-4

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.
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http://dx.doi.org/10.1016/s0960-894x(02)00604-2DOI Listing
November 2002

Nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase with potent antibacterial activity against gram-positive pathogens.

J Med Chem 2002 May;45(10):1959-62

Potent nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase have been derived from a file compound high throughput screening hit. Optimized compounds show excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics. Compound 11 demonstrated in vivo efficacy in an S. aureus rat abscess infection model.
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http://dx.doi.org/10.1021/jm025502xDOI Listing
May 2002