Publications by authors named "Andrew K Forrest"

8 Publications

  • Page 1 of 1

Virtual Screening Approach to Identifying a Novel and Tractable Series of Elastase Inhibitors.

ACS Med Chem Lett 2021 Feb 15;12(2):217-227. Epub 2021 Jan 15.

Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France.

Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is , which persists within the lungs of CF sufferers despite intensive antibiotic treatment. elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds and ( = 0.16 μM and 0.12 μM, respectively).
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http://dx.doi.org/10.1021/acsmedchemlett.0c00554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883467PMC
February 2021

Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles.

ACS Med Chem Lett 2017 Sep 25;8(9):936-940. Epub 2017 Aug 25.

Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.

A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound , an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of , a highly potent and selective inhibitor of PI3Kδ.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601369PMC
September 2017

Synthesis and properties of macrolones characterized by two ether bonds in the linker.

Bioorg Med Chem 2010 Sep 14;18(17):6578-88. Epub 2010 Jul 14.

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

In this paper synthesis of macrolones 1-18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C-C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4''-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C-C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.
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http://dx.doi.org/10.1016/j.bmc.2010.07.007DOI Listing
September 2010

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

Synthesis and activity of analogues of the isoleucyl tRNA synthetase inhibitor SB-203207.

Bioorg Med Chem 2003 Jul;11(13):2687-94

Research School of Chemistry, Institute of Advanced Studies, Australian National University, Canberra, ACT 0200, Australia.

Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.
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http://dx.doi.org/10.1016/s0968-0896(03)00237-2DOI Listing
July 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

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