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Featured researches published by Catherine Chabot.


Bioorganic & Medicinal Chemistry | 1999

Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy.

Bruno Simoneau; Pierre Lavallee; Paul C. Anderson; Murray D. Bailey; Gary W. Bantle; Sylvie Berthiaume; Catherine Chabot; Gulrez Fazal; Ted Halmos; William W. Ogilvie; Marc-André Poupart; Bounkham Thavonekham; Zhili Xin; Diane Thibeault; Gordon Bolger; Maret Panzenbeck; Raymond J. Winquist; Grace Jung

A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.


Pure and Applied Chemistry | 1996

Lewis acids in diastereoselective processes involving acyclic radicals

Yvan Guindon; Brigitte Guérin; Jean Rancourt; Catherine Chabot; Nicole Mackintosh; William W. Ogilvie

The radical reductions and allylations of a series of a-halo-P-alkoxy esters under bidentate chelation-controlled conditions are reported and compared with the analogous reactions under non-chelating conditions. The addition of Lewis acids is shown to give excellent selectivity for the syn products in the case of reduction, and the anti products in the case of allylation. In some cases, ratios greater than 1OO:l are obtained. The reactions require initiation with EbB and can be inhibited by m- and p-dinitrobenzene, which imply a radical-based mechanism. Iodides, bromides and phenyl selenides are all suitable substrates. Investigations also provide a rationale for the large excess of MgBr2.OEt2 which is apparently required in these reactions. Competition experiments provide a more detailed explanation of substrate reactivity. Traditionally radicals derived from acyclic precursors have seldom been considered as intermediates for the generation of asymmetric centers. Recently however, it has been discovered that radicals can indeed react with high levels of diastereoselectivity (1). This has been achieved mainly through the use of chiral auxiliaries (2) or by the influence of a stereogenic center adjacent to a carbonyl (1,2-asymmetric induction) (3,4, 5). The scope of these reactions has also been expanded by the use of Lewis acids (6, 7), solvent complexation (8) and intramolecular hydrogen bonding (9) to enhance and even reverse the facial bias. In this paper, we describe results we have obtained in chelation-controlled reductions, allylations and atom transfer reactions of a-halo-P-alkoxy esters, and present evidence for radical-based processes. Preliminary experiments designed to elucidate further mechanistic details will also be discussed. Scheme 1 X Ph -. *Et


Antiviral Chemistry & Chemotherapy | 1998

Potent β-Lactam Inhibitors of Human Cytomegalovirus Protease:

Christiane Yoakim; William W. Ogilvie; Cameron; Catherine Chabot; Chantal Grand-Maitre; Ingrid Guse; Bruno Haché; Stephen H. Kawai; Julie Naud; Jeff O'Meara; Raymond Plante; Robert Deziel

A series of novel monobactam inhibitors of human cytomegalovirus (HCMV) protease has been described that possess a heterocyclic thiomethyl side chain at C-4. Changes to the heterocycle did not significantly change the inhibitory activity of these compounds in an enzymatic assay, although improvements in solubility and cell culture activity were noted. A number of permutations between C-4 substitutions and N-1 derivatives led to the identification of several β-lactams with antiviral activity in a plaque reduction assay. N-methyl thiotetrazole-containing compounds were found to be the most potent inhibitors in the enzymatic assay.


Journal of Medicinal Chemistry | 2014

Conformation-Based Restrictions and Scaffold Replacements in the Design of Hepatitis C Virus Polymerase Inhibitors: Discovery of Deleobuvir (BI 207127)

Steven R. LaPlante; Michael Bös; Christian Brochu; Catherine Chabot; René Coulombe; James Gillard; Araz Jakalian; Martin Poirier; Jean Rancourt; Timothy Stammers; Bounkham Thavonekham; Pierre L. Beaulieu; George Kukolj; Youla S. Tsantrizos

Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.


Acta Crystallographica Section D-biological Crystallography | 2000

A rational approach towards successful crystallization and crystal treatment of human cytomegalovirus protease and its inhibitor complex

Chungeng Qian; Lisette Lagacé; Marie-Josée Massariol; Catherine Chabot; Christiane Yoakim; Robert Deziel; Liang Tong

The crystallization and subsequent crystal treatment of both free human cytomegalovirus (hCMV) protease and its inhibitor complexes are reported. For free-enzyme crystals, diffraction was greatly improved by optimizing the crystallization conditions, raising the precipitant concentration in the reservoir and soaking the crystals in artificial mother liquors. Each of the six components in the final crystallization formula (16% PEG 4000, 0.1 M MES pH 6.0, 0.4 M LiCl, 10% glycerol, 5% t-butanol and 5 mM Na(2)S(2)O(3)) plays a distinctive role and is indispensable. A synergistic effect of Na(2)SO(4) and t--butanol on diffraction was observed and studied. A 2.0 A multiwavelength anomalous diffraction (MAD) data set was collected using a synchrotron-radiation source, leading to the elucidation of the three-dimensional structure of the enzyme. For the inhibitor-complex crystals, initial attempts with co-crystallization and soaking experiments at pH 6.0 did not produce conclusive results. Subsequently, experiments were designed to co-crystallize the complex at pH 8.0, the optimal pH for the enzyme and the inhibitor activity. Using 20-50 mM spermine in the crystallization buffer, crystals of two peptidomimetic inhibitor complexes were obtained at pH 7.5 and 8.0. Spermine was required for the inhibitor complexes to be crystallized at pH 8.0, possibly neutralizing net negative charges of hCMV protease owing to its acidic pI of 5.5. A 2.7 A data set was collected from one of the inhibitor complexes and the structure was determined using the molecular-replacement method.


ACS Medicinal Chemistry Letters | 2014

Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

Lee Fader; Rebekah Carson; Sébastien Morin; Franco̧is Bilodeau; Catherine Chabot; Ted Halmos; Murray D. Bailey; Stephen H. Kawai; René Coulombe; Steven R. LaPlante; Kevork Mekhssian; Araz Jakalian; Michel Garneau; Jianmin Duan; Stephen W. Mason; Bruno Simoneau; Craig Fenwick; Youla S. Tsantrizos; Christiane Yoakim

A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC50 values <10 nM against viruses having T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs.


Bioorganic & Medicinal Chemistry Letters | 2011

Indole 5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): Central amino acid linker and right-hand-side SAR studies

Pierre L. Beaulieu; Catherine Chabot; Jianmin Duan; Michel Garneau; James Gillard; Eric Jolicoeur; Martin Poirier; Marc-André Poupart; Timothy Stammers; George Kukolj; Youla S. Tsantrizos

In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC(50)<100 nM), physicochemical properties and ADME characteristics.


ACS Medicinal Chemistry Letters | 2016

Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.

Lee Fader; Murray D. Bailey; Eric Beaulieu; François Bilodeau; Pierre R. Bonneau; Yves Bousquet; Rebekah Carson; Catherine Chabot; René Coulombe; Jianmin Duan; Craig Fenwick; Michel Garneau; Ted Halmos; Araz Jakalian; Clint James; Stephen H. Kawai; Serge Landry; Steven R. LaPlante; Stephen W. Mason; Sébastien Morin; Nathalie Rioux; Bruno Simoneau; Simon Surprenant; Bounkham Thavonekham; Carl Thibeault; Thao Trinh; Youla S. Tsantrizos; Jennifer Tsoung; Christiane Yoakim; Dominik Wernic

Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.


Archive | 2007

Viral polymerase inhibitors

Youla S. Tsantrizos; Catherine Chabot; Pierre L. Beaulieu; Christian Brochu; Martin Poirier; Timothy Stammers; Bounkham Thavonekham; Jean Rancourt


Journal of Medicinal Chemistry | 1998

β-Lactam derivatives as inhibitors of human cytomegalovirus protease

Christiane Yoakim; William W. Ogilvie; Dale R. Cameron; Catherine Chabot; Ingrid Guse; Bruno Haché; Julie Naud; Jeff O'Meara; Raymond Plante; Robert Deziel

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