Publications by authors named "Clement Douault"

7 Publications

  • Page 1 of 1

Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors.

Bioorg Med Chem Lett 2016 10 23;26(19):4606-4612. Epub 2016 Aug 23.

AstraZeneca, Hodgkin Building, Chesterford Research Campus, Little Chesterford, Saffron Walden, Cambs. CB10 1XL, UK.

The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.
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http://dx.doi.org/10.1016/j.bmcl.2016.08.070DOI Listing
October 2016

A Chemical Probe for the ATAD2 Bromodomain.

Angew Chem Int Ed Engl 2016 09 17;55(38):11382-6. Epub 2016 Aug 17.

GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.
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http://dx.doi.org/10.1002/anie.201603928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314595PMC
September 2016

Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives.

J Med Chem 2016 Feb 15;59(4):1357-69. Epub 2016 Jan 15.

Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.

Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).
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http://dx.doi.org/10.1021/acs.jmedchem.5b01537DOI Listing
February 2016

Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.

J Med Chem 2015 Aug 31;58(15):6151-78. Epub 2015 Jul 31.

∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00773DOI Listing
August 2015

Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors.

J Med Chem 2015 Jul 9;58(14):5649-73. Epub 2015 Jul 9.

∥Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, United Kingdom.

Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00772DOI Listing
July 2015

Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor.

Bioorg Med Chem Lett 2011 Oct 12;21(20):6188-94. Epub 2011 Aug 12.

GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK.

The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
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http://dx.doi.org/10.1016/j.bmcl.2011.07.082DOI Listing
October 2011

Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain.

Bioorg Med Chem Lett 2010 Aug 31;20(15):4683-8. Epub 2010 May 31.

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.
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http://dx.doi.org/10.1016/j.bmcl.2010.05.026DOI Listing
August 2010