Merck Frosst Canada Ltd.
Merck Frosst Canada Ltd.
Becker J.M.,University of Tennessee at Knoxville |
Kauffman S.J.,University of Tennessee at Knoxville |
Hauser M.,University of Tennessee at Knoxville |
Huang L.,University of Tennessee at Knoxville |
And 5 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010
One potentially rich source of possible targets for antifungal therapy are those Candida albicans genes deemed essential for growth under the standard culture (i.e., in vitro) conditions; however, these genes are largely unexplored as drug targets because essential genes are not experimentally amenable to conventional gene deletion and virulence studies. Using tetracycline-regulatable promoter-based conditional mutants, we investigated a murine model of candidiasis in which repressing essential genes in the host was achieved. By adding doxycycline to the drinking water starting 3 days prior to (dox - 3D) or 2 days post (dox + 2D) infection, the phenotypic consequences of temporal gene inactivation were assessed by monitoring animal survival and fungal burden in prophylaxis and acute infection settings. Of 177 selected conditional shut- off strains tested, the virulence of 102 was blocked under both repressing conditions, suggesting that the corresponding genes are essential for growth and survival in a murine host across early and established infection periods. Among these genes were those previously identified as antifungal drug targets (i.e., FKS1, ERG1, and ERG11), verifying that this methodology can be used to validate potential new targets. We also identify genes either conditionally essential or dispensable for in vitro growth but required for survival and virulence, including those in late stage ergosterol synthesis, or early steps in fatty acid or riboflavin biosynthesis. This study evaluates the role of essential genes with respect to pathogen virulence in a large-scale, systems biology context, and provides a general method for gene target validation and for uncovering unexpected antimicrobial targets.
Merck Frosst Canada Ltd. and Axys Pharmaceuticals Inc. | Date: 2014-05-20
This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
Moran E.E.,Concordia University at Montréal |
Timerghazin Q.K.,Concordia University at Montréal |
Timerghazin Q.K.,Marquette University |
Kwong E.,Merck Frosst Canada Incorporated |
English A.M.,Concordia University at Montréal
Journal of Physical Chemistry B | Year: 2011
The denitrosation of three primary S-nitrosothiols (RSNO; S-nitrosocysteine, S-nitroso-N-acetylcysteine, and S-nitrosoglutathione) and two tertiary RSNOs (S-nitrosopenicillamine and S-nitroso-N-acetylpenicillamine) was investigated in 3.75 M H2SO4 to probe the mechanism of acid-catalyzed RSNO hydrolysis and its dependence on RSNO structure. This reversible reaction was forced to proceed in the denitrosation direction by trapping the nitrosating agent with HN3. The primary RSNOs exhibited hydrolysis kobs values of ∼2 × 10-4 s -1, and the tertiary RSNO kobs values were an order of magnitude higher. Product analysis by HPLC revealed that the parent thiols (RSHs) were formed in 90-100% yield on 79-99% RSNO denitrosation. Possible hydrolysis mechanisms were studied computationally at the CBS-QB3 level using S-nitrosomethanethiol (MeSNO) as a model RSNO. Consideration of RSNOs as a combination of conventional R-S-N=O, zwitterionic R-S+=N-O -, and RS-/NO+ ion-pair resonance structures was key in understanding the mechanistic details of acid-catalyzed hydrolysis. Protonation of the S-nitroso oxygen or nitrogen activates the sulfur and nucleophilic attack by H2O at this atom leads to the formation of the sulfoxide-protonated N-hydroxysulfinamide, MeS+(OH)NHOH, with barriers of 19 and 29 kcal/mol, respectively. Proton loss and reprotonation at the nitrogen lead to secondary hydrolysis that produces the sulfinic acid MeS(=O)OH and NH2OH. Notably, no low-energy RSNO hydrolysis pathway for HNO release was found in the computational analysis. Protonation of the S-nitroso sulfur gives rise to NO+ release with a low activation barrier (ΔH‡calc ≈ 6 kcal/mol) and the formation of MeSH in agreement with experiment. The experimental kobs can be expressed as Kak1, where Ka is the acid dissociation constant for protonation of the S-nitroso sulfur and k1 the pseudo-first-order hydrolysis rate constant. Given the low ΔH ‡calc for denitrosation of the S-protonated isomer, the observed slow rates of acid-catalyzed RSNO hydrolysis must be controlled by the magnitude of Ka. The 10-fold higher Ka calculated for Me3CS(H+)NO (∼10-15) compared to MeS(H+)NO (10-16) is consistent with the order of magnitude larger kobs reported here for the tertiary vs primary RSNOs. © 2011 American Chemical Society.
Kesting J.R.,Copenhagen University |
Huang J.,Merck Frosst Canada Ltd. |
Sorensen D.,Merck Frosst Canada Ltd.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2010
Based on anecdotal evidence of anti-hypertensive effect of Gold Nine Soft Capsules, an in vivo study of this complex Chinese "herbal-based" medicine was initiated. Dosage of the content of Gold Nine capsules in spontaneous hypertensive rats showed a remarkably good effect. This led to further investigation of the components of the preparation and eventual identification of three known anti-hypertensive drugs; amlodipine, indapamide and valsartan, which were not declared on the label. Compounds were rapidly identified using LC-HRMS and LC-MS-SPE/NMR, quantified by HPLC, and the in vivo activity of a combination of commercially purchased standards was shown to be equivalent to that of the capsule content. Adulteration of herbal remedies and dietary supplements with synthetic drugs is an increasing problem that may lead to serious adverse effects. LC-MS-SPE/NMR as a method for the rapid identification of such adulterants is highlighted in this case study. © 2009 Elsevier B.V. All rights reserved.
Bouffard J.,Ecole Polytechnique de Montréal |
Bertrand F.,Ecole Polytechnique de Montréal |
Chaouki J.,Ecole Polytechnique de Montréal |
Dumont H.,Merck Frosst Canada Ltd.
Computers and Chemical Engineering | Year: 2013
Powder flow in a spheronizer is characterized by a toroidal motion and the flow patterns depend on the disc velocity and the fill level, but also on the particle properties. This work investigates numerically, with a discrete element method (DEM), the impact of these parameters on segregation patterns and the flow dynamics for bidisperse particle size distributions. Characterization of the segregation, by means of a mixing index and the relation with the shear stress in the toroidal domain, is presented. Characteristics, such as mixing curves, concentration profiles and azimuthal velocity correlations, are discussed. A logarithmic expression has been developed to account for the shear stress on the evolution of the azimuthal velocity inside the particulate bed. The combination of the mixing indexes and the concentration profiles is used to quantify the changes observed on the segregation when the fill level and the rotational rate of the spheronizer disk are varied. © 2012 Elsevier Ltd.
Merck Frosst Canada Ltd. | Date: 2011-10-10
The present invention relates to renin inhibitor compounds having the structure and their use in treating cardiovascular events and renal insufficiency.
Merck Frosst Canada Ltd | Date: 2011-04-06
Merck Frosst Canada Ltd. | Date: 2010-03-18
Heterocyclic compounds of structural formula I are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD). The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease; atherosclerosis; obesity; diabetes; neurological disease; Metabolic Syndrome; insulin resistance; cancer, liver steatosis; and non-alcoholic steatohepatitis.
Merck Frosst Canada Ltd | Date: 2011-03-16
Compositions containing fluoro substituted cycloalkanoindole derivatives of formula I are antagonists of prostaglandins, and as such are useful for the treatment of prostaglandin mediated diseases.
Merck Frosst Canada Ltd. | Date: 2013-04-11
Several parasites responsible for mammalian diseases are dependent on cysteine protease for various life-cycle functions. Inhibition or decreasing function of these proteases can be useful in the treatment and/or prevention of these parasitic diseases including; toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, ascariasis, trichuriasis, stronglyoidiasis, trichostrongyliasis, trichomoniasis or cestodiasis.