-
[show abstract]
[hide abstract]
ABSTRACT: A series of dipeptide nitriles with a thienyl alanine in P2 were identified as potent and selective cathepsin C inhibitors. Incorporation of a substituted cyclopropyl moiety in P1 effectively protects these derivatives against hydrolase activity in whole blood.
Bioorganic & medicinal chemistry letters 08/2009; 19(18):5392-6. · 2.65 Impact Factor
-
Nathalie Méthot,
Daniel Guay,
Joel Rubin,
Diane Ethier,
Karen Ortega,
Simon Wong,
Denis Normandin,
Christian Beaulieu, T Jagadeeswar Reddy,
Denis Riendeau,
M David Percival
[show abstract]
[hide abstract]
ABSTRACT: Inhibition of cathepsin C, a dipeptidyl peptidase that activates many serine proteases, represents an attractive therapeutic strategy for inflammatory diseases with a high neutrophil burden. We recently showed the feasibility of blocking the activation of neutrophil elastase, cathepsin G, and proteinase-3 with a single cathepsin C selective inhibitor in cultured cells. Here we measured the fractional inhibition of cathepsin C that is required for blockade of downstream serine protease processing, in cell-based assays and in vivo. Using a radiolabeled active site probe and U937 cells, a 50% reduction of cathepsin G processing required approximately 50% of cathepsin C active sites to be occupied by an inhibitor. In EcoM-G cells, inhibition of 50% of neutrophil elastase activity required approximately 80% occupancy. Both of these serine proteases were fully inhibited at full cathepsin C active site occupancy, whereas granzyme B processing in TALL-104 cells was partially inhibited, despite complete occupancy. In vivo, leukocytes from cathepsin C(+/-) mice exhibited comparable levels of neutrophil elastase activity to wild-type animals, even though their cathepsin C activity was reduced by half. The long-term administration of a cathepsin C inhibitor to rats, at doses that resulted in the nearly complete blockade of cathepsin C active sites in bone marrow, caused significant reductions of neutrophil elastase, cathepsin G and proteinase-3 activities. Our results demonstrate that the inhibition of cathepsin C leads to a decrease of activity of multiple serine proteases involved in inflammation but also suggest that high fractional inhibition is necessary to reach therapeutically significant effects.
Molecular pharmacology 07/2008; 73(6):1857-65. · 4.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cathepsin C is a cysteine protease required for the activation of several pro-inflammatory serine proteases and, as such, is of interest as a therapeutic target. In cathepsin C-deficient mice and humans, the N-terminal processing and activation of neutrophil elastase, cathepsin G, and proteinase-3 is abolished and is accompanied by a reduction of protein levels. Pharmacologically, the consequence of cathepsin C inhibition on the activation of these serine proteases has not been described, due to the lack of stable and non-toxic inhibitors and the absence of appropriate experimental cell systems. Using novel reversible peptide nitrile inhibitors of cathepsin C, and cell-based assays with U937 and EcoM-G cells, we determined the effects of pharmacological inhibition of cathepsin C on serine protease activity. We show that indirect and complete inhibition of neutrophil elastase, cathepsin G, and proteinase-3 is achievable in intact cells with selective and non-cytotoxic cathepsin C inhibitors, at concentrations approximately 10-fold higher than those required to inhibit purified cathepsin C. The concentration of inhibitor needed to block processing of these three serine proteases was similar, regardless of the cell system used. Importantly, cathepsin C inhibition must be sustained to maintain serine protease inhibition, because removal of the reversible inhibitors resulted in the activation of pro-enzymes in intact cells. These findings demonstrate that near complete inhibition of multiple serine proteases can be achieved with cathepsin C inhibitors and that cathepsin C inhibition represents a viable but challenging approach for the treatment of neutrophil-based inflammatory diseases.
Journal of Biological Chemistry 08/2007; 282(29):20836-46. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A 13-step synthesis of (+)-cyanthiwigin-AC (2) from (+)-Hajos-Parrish ketone derivative 8b and dimesylate 9c employing deconjugative spiro-bis-alkylation strategy is described. [reaction: see text].
Organic Letters 12/2006; 8(24):5585-8. · 5.86 Impact Factor
-
Constantin G Yannopoulos,
Ping Xu,
Feng Ni,
Laval Chan,
Oswy Z Pereira, T Jagadeeswar Reddy,
Sanjoy K Das,
Carl Poisson,
Nghe Nguyen-Ba,
Nathalie Turcotte, [......],
Lilianne Halab,
Wuyi Wang,
Jean Bédard,
Nicolas Morin,
Martine Hamel,
Olivier Nicolas,
Darius Bilimoria,
Lucille L'Heureux,
Richard Bethell,
Gervais Dionne
[show abstract]
[hide abstract]
ABSTRACT: HCV NS5B RNA-dependent RNA polymerase (NS5B) is essential for viral replication and is therefore considered a target for antiviral drug development. From our ongoing screening effort in the search for new anti-HCV agents, a novel inhibitor 1 with low microM activity against the HCV NS5B polymerase was identified. SAR analysis indicated the optimal substitution pattern required for activity, for example, carboxylic acid group at 2-position of thiophene ring. We describe the steps taken to identify and solve the bioactive conformation of derivative 6 through the use of the transferred NOE method (trNOE).
Bioorganic & Medicinal Chemistry Letters 12/2004; 14(21):5333-7. · 2.55 Impact Factor
-
Laval Chan,
Sanjoy K Das, T Jagadeeswar Reddy,
Carl Poisson,
Mélanie Proulx,
Oswy Pereira,
Marc Courchesne,
Caroline Roy,
Wuyi Wang,
Arshad Siddiqui, [......],
Denis Labrecque,
Richard Bethell,
Martine Hamel,
Philippe Courtemanche-Asselin,
Lucille L'Heureux,
Maud David,
Olivier Nicolas,
Stéphanie Brunette,
Darius Bilimoria,
Jean Bédard
[show abstract]
[hide abstract]
ABSTRACT: The discovery of a novel class of HCV NS5B polymerase inhibitors, 3-arylsulfonylamino-5-phenyl-thiophene-2-carboxylic acids is described. SAR studies have yielded several potent inhibitors of HCV polymerase as well as of HCV subgenomic RNA replication in Huh-7 cells.
Bioorganic & Medicinal Chemistry Letters 03/2004; 14(3):793-6. · 2.55 Impact Factor
-
Laval Chan,
Oswy Pereira, T Jagadeeswar Reddy,
Sanjoy K Das,
Carl Poisson,
Marc Courchesne,
Mélanie Proulx,
Arshad Siddiqui,
Constantin G Yannopoulos,
Nghe Nguyen-Ba, [......],
Christophe Moinet,
Richard Bethell,
Martine Hamel,
Lucille L'Heureux,
Maud David,
Olivier Nicolas,
Philippe Courtemanche-Asselin,
Stéphanie Brunette,
Darius Bilimoria,
Jean Bédard
[show abstract]
[hide abstract]
ABSTRACT: Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies.
Bioorganic & Medicinal Chemistry Letters 03/2004; 14(3):797-800. · 2.55 Impact Factor
-
T Jagadeeswar Reddy,
Laval Chan,
Nathalie Turcotte,
Melanie Proulx,
Oswy Z Pereira,
Sanjoy K Das,
Arshad Siddiqui,
Wuyi Wang,
Carl Poisson,
Constantin G Yannopoulos,
Darius Bilimoria,
Lucille L'Heureux,
Hicham M A Alaoui,
Nghe Nguyen-Ba
[show abstract]
[hide abstract]
ABSTRACT: Herein, we describe the structure-activity relationship (SAR) of N,N-disubstituted phenylalanine series of NS5B polymerase inhibitors of hepatitis C. The NS5B polymerase inhibitory activity of the most active compound exhibited an IC(50) of 2.7 microM.
Bioorganic & Medicinal Chemistry Letters 11/2003; 13(19):3341-4. · 2.55 Impact Factor
-
Laval Chan, T Jagadeeswar Reddy,
Mélanie Proulx,
Sanjoy K Das,
Oswy Pereira,
Wuyi Wang,
Arshad Siddiqui,
Constantin G Yannopoulos,
Carl Poisson,
Nathalie Turcotte,
Alexandre Drouin,
M Hicham Alaoui-Ismaili,
Richard Bethell,
Martine Hamel,
Lucille L'Heureux,
Darius Bilimoria,
Nghe Nguyen-Ba
[show abstract]
[hide abstract]
ABSTRACT: The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and structure-activity relationships studies to improve potency are described.
Journal of Medicinal Chemistry 05/2003; 46(8):1283-5. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In this paper we describe the syntheses of the tetraoxygenated triarylmethyl (trityl) radical 14 and the tetrathiatriarylmethyl (trityl) radicals 15 and 16. The syntheses include new and improved preparations of the key intermediate compounds 1 and 2. The new route to compound 2 is noteworthy for its efficiency and its avoidance of the highly toxic compound phosgene as well as the isolation of the air-sensitive 1,2,4,5-benzenetetrathiol.
The Journal of Organic Chemistry 08/2002; 67(14):4635-9. · 4.45 Impact Factor
