Merck Frosst Center for Therapeutic Research

Kirkland, Canada

Merck Frosst Center for Therapeutic Research

Kirkland, Canada
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Guay D.,Merck Frosst Center for Therapeutic Research | Beaulieu C.,Merck Frosst Center for Therapeutic Research | Percival M.D.,Merck Frosst Center for Therapeutic Research
Current Topics in Medicinal Chemistry | Year: 2010

The lysosomal cysteine protease cathepsin C (Cat C), also known as dipeptidyl peptidase I, activates a number of granule-associated serine proteases with pro-inflammatory and immune functions by removal of their inhibitory N- terminal dipeptides. Thus, Cat C is a therapeutic target for the treatment of a number of inflammatory and autoimmune diseases. Cathepsin C null mice and humans with Cat C loss of function mutations (Papillon-Lefèvre syndrome) show deficiencies in disease-relevant proteases including neutrophil elastase, cathepsin G, chymases and granzymes and the Cat C mice are protected in a number of disease models. Several methodologies have been recently reported for assessing the effects of Cat C inhibitors on serine protease activities in cellular assays and prolonged treatment of rats with a reversible, selective Cat C inhibitor reduced the activity of three leukocyte serine proteases. Nearly all potent and selective Cat C inhibitors described are based on the preferred dipeptide substrates bearing either irreversible (e.g. diazomethylketone, acyloxymethyl ketone, o-acyl hydroxamic acid and vinyl sulfone) or reversible (e.g. semicarbazide, nitrile and cyanamide) electrophilic warheads. While potent and highly selective, the best inhibitors described to date still have poor stability and/or rodent pharmacokinetics, likely resulting from their peptidic nature. The lack of selective compounds with appropriate rodent pharmacokinetic properties has hampered the assessment of the effects of Cat C inhibitors on the activation of disease-relevant proteases in vivo and the full evaluation of the therapeutic utility of Cat C inhibitors. © 2010 Bentham Science Publishers Ltd.


Black W.C.,Merck Frosst Center for Therapeutic Research
Current Topics in Medicinal Chemistry | Year: 2010

Cathepsin K (Cat K) is the primary enzyme involved in Type I collagen degradation in bone resorption. The development of a Cat K inhibitor should provide an effective treatment for osteoporosis. Key components of a clinically viable inhibitor are oral bioavailability, high selectivity over related cathepsins, and a covalent, reversible warhead to bind to the active site cysteine of the enzyme. This article reviews recent advances in the design of inhibitors derived from peptidic leads that contain either a ketone or nitrile electrophile. Three of these compounds have progressed into clinical trials and one, odanacatib (5), is currently in Phase III studies for the treatment of post-menopausal osteoporosis. © 2010 Bentham Science Publishers Ltd.


Wang H.,Merck Frosst Center for Therapeutic Research | Claveau D.,Merck Frosst Center for Therapeutic Research | Vaillancourt J.P.,Merck Frosst Center for Therapeutic Research | Roemer T.,Merck Frosst Center for Therapeutic Research | And 2 more authors.
Nature Chemical Biology | Year: 2011

Connecting bacterial growth inhibitors to molecular targets at the whole-cell level is a major impediment to antibacterial development. Herein we report the design of a highly efficient and versatile bacteriophage-based mariner transposon delivery system in Staphylococcus aureus for determining inhibitor mode of action. Using bacteriophage-mediated delivery of concatameric minitransposon cassettes, we generated nonclonal transposant libraries with genome-wide insertion-site coverage in either laboratory or methicillin- resistant strain backgrounds and screened for drug resistance in situ on a single agar plate in one step. A gradient of gene-target expression levels, along with a correspondingly diverse assortment of drug-resistant phenotypes, was achieved by fitting the transposon cassette with a suite of outward-facing promoters. Using a panel of antibiotics, we demonstrate the ability to unveil not only an inhibitor's molecular target but also its route of cellular entry, efflux susceptibility and other off-target resistance mechanisms. © 2011 Nature America, Inc. All rights reserved.


Levesque P.,Merck Frosst Center for Therapeutic Research | Fournier P.-A.,Merck Frosst Center for Therapeutic Research
Journal of Organic Chemistry | Year: 2010

A mild, efficient, and simple method for the synthesis of 3-ethoxycarbonylindoles has been developed. Addition of ethyl diazoacetate (EDA) to 2-aminobenzaldehydes cleanly affords the indole core. As opposed to other common approaches for the synthesis of indole, this method displays both excellent functional group tolerance and perfect regiochemical control. This allowed the synthesis of a variety of useful indole building blocks from 2-aminobenzaldehydes derived from readily available anthranilic acids. © 2010 American Chemical Society.


Li L.,Merck Frosst Center for Therapeutic Research | Chua W.K.S.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2011

We have developed a robust approach for the synthesis of 3,4-fused isoquinolin-1(2H)-one analogs. A benzonitrile or a nicotinonitrile bearing an ortho-substituent, such as -OH, -SH, or -NHR (R = alkyl or aryl) can be deprotonated by KOtBu and then reacted with methyl 2-(bromomethyl)benzoate (8) to form its corresponding O-, S-, or N-alkylation product. The product thus formed is then treated with KOtBu again to initiate a cascade process that will lead to the formation of its corresponding 3,4-fused isoquinolin-1(2H)-one. This multistep synthesis as well as the final product purification is achieved in a one-pot manner. © 2011 Elsevier Ltd. All rights reserved.


Li L.,Merck Frosst Center for Therapeutic Research | Chua W.K.S.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2011

We have developed an efficient one-pot multistep sequence to the synthesis of 3-aminoindolizine derivatives by using Hantzsch ester (9) as a mild hydride transfer agent. The reaction scope was investigated and the effect of substrates on reaction outcomes was discussed.


Truong V.L.,Merck Frosst Center for Therapeutic Research | Morrow M.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2010

Condensation of o-iodobenzaldehydes 1a_c with amidine hydrochlorides 2a_p under ligand-free copper-catalyzed Ullmann N-arylation conditions afforded the corresponding quinazolines 3a-r in good to excellent yields. © 2009 Elsevier Ltd. All rights reserved.


Molinaro C.,Merck Frosst Center for Therapeutic Research | Guilbault A.-A.,Merck Frosst Center for Therapeutic Research | Kosjek B.,Merck And Co.
Organic Letters | Year: 2010

A practical procedure for the enzymatic resolution of 2-alkyl-2-aryl- disubstituted epoxides using the Codex HHDH P2E2 enzyme and sodium azide is reported. This method allowed the synthesis of novel regio-and enantioselective 1-azido-2-arylpropan-2-ols in excellent yields. Furthermore, these intermediates were used for the preparation of enantiomerically enriched amino alcohols and aziridines containing a tertiary center. © 2010 American Chemical Society.


Christian N.,Merck Frosst Center for Therapeutic Research | Aly S.,Merck Frosst Center for Therapeutic Research | Belyk K.,Merck And Co.
Journal of the American Chemical Society | Year: 2011

The highly enantioselective catalytic asymmetric addition of aryl and alkenylboronic acids to N-benzylnicotinate salt 1 is described. The dihydropyridine 2 reaction products can be converted to synthetically useful piperidines. Application of the methodology to the preparation of enantioenriched quaternary chiral centers is also discussed. © 2011 American Chemical Society.


Powell D.A.,Merck Frosst Center for Therapeutic Research | Fan H.,Merck Frosst Center for Therapeutic Research
Journal of Organic Chemistry | Year: 2010

A room-temperature, copper-catalyzed amination of primary benzylic C?H bonds with primary and secondary sulfonamides is described. The reaction is applicable to the coupling of a range of primary and secondary benzylic hydrocarbons with a diverse set of sulfonamides and is tolerant of substitution on both coupling partners. Factors which influence the selectivity of C?H functionalization between primary and secondary sites are examined. © 2010 American Chemical Society.

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