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Elise Isabel,
Christophe Mellon,
Michael J Boyd,
Nathalie Chauret,
Denis Deschênes,
Sylvie Desmarais,
Jean-Pierre Falgueyret,
Jacques Yves Gauthier,
Karine Khougaz,
Cheuk K Lau, [......],
Frédéric Massé,
M David Percival, Bruno Roy,
John Scheigetz,
Michel Thérien,
Vouy Linh Truong,
Gregg Wesolowski,
Robert N Young,
Robert Zamboni,
W Cameron Black
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ABSTRACT: The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.
Bioorganic & medicinal chemistry letters 02/2011; 21(3):920-3. · 2.65 Impact Factor
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Claudio F Sturino,
Gary O'Neill,
Nicolas Lachance,
Michael Boyd,
Carl Berthelette,
Marc Labelle,
Lianhai Li, Bruno Roy,
John Scheigetz,
Nancy Tsou, [......],
Deborah Slipetz,
William M Abraham,
Tom Jones,
Malia McAuliffe,
Hana Piechuta,
Deborah A Nicoll-Griffith,
Zhaoyin Wang,
Robert Zamboni,
Robert N Young,
Kathleen M Metters
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ABSTRACT: The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.
Journal of Medicinal Chemistry 03/2007; 50(4):794-806. · 5.25 Impact Factor
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Claudio F Sturino,
Nicolas Lachance,
Michael Boyd,
Carl Berthelette,
Marc Labelle,
Lianhai Li, Bruno Roy,
John Scheigetz,
Nancy Tsou,
Christine Brideau, [......],
Stacia Kargman,
Sonia Lamontagne,
Marie-Claude Mathieu,
Nicole Sawyer,
Deborah Slipetz,
Gary O'Neill,
Zhaoyin Wang,
Robert Zamboni,
Kathleen M Metters,
Robert N Young
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ABSTRACT: A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed.
Bioorganic & Medicinal Chemistry Letters 07/2006; 16(11):3043-8. · 2.55 Impact Factor
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Claudio F. Sturino, Nicolas Lachance,
Michael Boyd,
Carl Berthelette,
Marc Labelle, Lianhai Li, Bruno Roy,
John Scheigetz,
Nancy Tsou,
Christine Brideau, Elizabeth Cauchon,
Marie-Claude Carriere
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ABSTRACT: A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6nM, respectively. The structure–activity relationships of this indole series of DP receptor antagonists will also be discussed.
Bioorganic & Medicinal Chemistry Letters - BIOORG MEDICINAL CHEM LETTER. 01/2006; 16(11):3043-3048.
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David A. Conlon,
Antoinette Drahus-Paone,
Guo-Jie Ho,
Brenda Pipik,
Roy Helmy,
James M. McNamara,
Yao-Jun Shi,
J. Michael Williams,
Dwight Macdonald,
Denis Deschênes,
Michel Gallant,
Anthony Mastracchio, Bruno Roy,
John Scheigetz
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ABSTRACT: An efficient, scalable synthesis of the PDE4 inhibitor, 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl)quinoline benzenesulfonate (10) is described. The synthesis is highly convergent, generating the penultimate 9 by coupling aldehyde 7 and oxadiazole 8 in a Knoevenagel reaction. The process consists of a total of nine chemical steps, five of which comprise the sequence to prepare aldehyde 7 via Skraup reaction, bromination, sulfone formation, methylation and Suzuki−Miyaura cross-coupling, and a two-step sequence for the synthesis of oxadiazole 8 that includes the methylamidoxime and oxadiazole steps. The final two steps are Knoevenagel coupling and salt formation. The process produced the drug candidate 10 in 46% overall yield from 2-bromo-4-methylaniline (1) on multikilogram scale.
12/2005;
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Dwight Macdonald,
Anthony Mastracchio,
Hélène Perrier,
Daniel Dubé,
Michel Gallant,
Patrick Lacombe,
Denis Deschênes, Bruno Roy,
John Scheigetz,
Kevin Bateman, [......],
Chi Chung Chan,
Angela Styhler,
Stella Charleson,
Joseph Mancini,
Paul Masson,
David Claveau,
Donald Nicholson,
Mervyn Turner,
Robert N Young,
Yves Girard
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ABSTRACT: The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
Bioorganic & Medicinal Chemistry Letters 12/2005; 15(23):5241-6. · 2.55 Impact Factor
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Michel Belley,
Michel Gallant, Bruno Roy,
Karine Houde,
Nicolas Lachance,
Marc Labelle,
Laird A Trimble,
Nathalie Chauret,
Chun Li,
Nicole Sawyer,
Nathalie Tremblay,
Sonia Lamontagne,
Marie-Claude Carrière,
Danielle Denis,
Gillian M Greig,
Deborah Slipetz,
Kathleen M Metters,
Robert Gordon,
Chi Chung Chan,
Robert J Zamboni
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ABSTRACT: A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.
Bioorganic & Medicinal Chemistry Letters 03/2005; 15(3):527-30. · 2.55 Impact Factor
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Erich L Grimm, Bruno Roy,
Renee Aspiotis,
Christopher I Bayly,
Donald W Nicholson,
Dita M Rasper,
Johanne Renaud,
Sophie Roy,
John Tam,
Paul Tawa,
John P Vaillancourt,
Steven Xanthoudakis,
Robert J Zamboni
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ABSTRACT: A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.
Bioorganic & Medicinal Chemistry 04/2004; 12(5):845-51. · 2.92 Impact Factor
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ABSTRACT: Tritium labeled 2,3,4,9-tetrahydro-1H-carbazole 1a and 2a were prepared in good yields with a specific activity of 7.0 Ci/mmol (214 GBq/mmol) and 4.2 Ci/mmol (155 GBq/mmol), respectively. Both compounds have been synthesized in high radiochemical purity by catalytic tritium–bromine exchange of the corresponding aryl bromide precursors. The 6-bromocarbazole precursors 7 and 8 were prepared as a mixture by a three step process, involving regioselective bromination of 3c with pyridinium tribromide, oxidation of thioether 4c using m-CPBA and hydrolysis of acylsultamcarbazole 5c. Finally, HPLC separation of the enantiomers afforded the 6-bromo precursors 7 and 8 in high diastereomeric ratio (dr 99% and dr 93% respectively). Copyright © 2004 John Wiley & Sons, Ltd.
Journal of Labelled Compounds 01/2004; 47(2):107 - 113.
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ABSTRACT: We have characterized some novel caged fluorescein diphosphates as photoactivatable, cell-permeable substrates for protein tyrosine phosphatases and explored their usefulness in identifying inhibitors of tyrosine phosphatases. 1-(2-Nitrophenyl)ethyl protected fluorescein diphosphate (NPE-FDP) undergoes rapid photolysis to release FDP upon irradiation with a 450-W UV immersion lamp and its by-product does not inactivate protein tyrosine phosphatase 1B (PTP1B) or alters the viability of cells. The generated FDP from photolysis of NPE-FDP was shown to have exactly the same properties as FDP, which can be used as a PTP substrate in pure enzyme assays. We have also demonstrated that the PTP activity can be measured using NPE-FDP in small droplets. Its advantage as an inert substrate before photolysis allows the possibility of applying nanospray technology in screening and optimizing PTP inhibitors through a large chemical library. Like other caged bioeffectors such as nucleotide and inositol trisphosphate, NPE-FDP is cell-permeable. The NPE-FDP can be photolyzed to generate FDP inside cells, and then can be hydrolyzed by phosphatases to produce fluorescein monophosphate and subsequently to fluorescein. Although Jurkat cells contain high concentrations of CD45, it has not been possible to use FDP as a substrate to measure CD45 activity in the intact cell. This is due to the hydrolysis of FDP by several other cellular phosphatases. However, NPE-FDP can be useful as a cell-permeable substrate for overexpressed phosphatases such as alkaline phosphatase.
Biochimica et Biophysica Acta 12/2002; 1601(1):19-28. · 4.66 Impact Factor
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ABSTRACT: Fluorescein phosphorotriesters 5, each having four identical photoactivatable adducts have been synthesized to investigate their applications as intracellular fluorescence indicators.
Synthetic Communications - SYN COMMUN. 01/2000; 30(8):1437-1445.
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Organic Preparations and Procedures International 12/1995; 27(6):637-644. · 1.01 Impact Factor
