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ABSTRACT: Cysteine cathepsins play an important role in many (patho)physiological conditions. Among them, cathepsins L, S, K and B are subjects of several drug discovery programs. Besides their role as drug targets, cysteine cathepsins are additionally considered to be possible biomarkers for inflammation and cancer. Herein, we describe the design, synthesis, biological evaluation and spectral properties of fluorescently labeled dipeptide- and azadipeptide nitriles.
Bioorganic & medicinal chemistry letters 10/2012; · 2.65 Impact Factor
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ABSTRACT: A series of dipeptide nitriles with different P3 substituents was designed to explore the S3 binding pocket of cathepsin S. Racemic 7-16 and the enantiopure derivative (R)-22 proved to be potent inhibitors of human cathepsin S and exhibited notable selectivity over human cathepsins L, K, and B. Inhibition of cathepsin F, the functional synergist of cathepsin S, was not observed. The azadipeptide analogue of 22, compound 26, was highly potent but nonselective.
Journal of Medicinal Chemistry 06/2012; 55(12):5982-6. · 4.80 Impact Factor
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Chemistry 09/2011; 17(41):11419-23. · 5.93 Impact Factor
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Santos Fustero,
Vanessa Rodrigo,
María Sánchez-Roselló,
Carlos del Pozo,
Joaquín Timoneda, Maxim Frizler,
Mihiret T Sisay,
Jürgen Bajorath,
Luis P Calle,
F Javier Cañada,
Jesús Jiménez-Barbero,
Michael Gütschow
Chemistry 03/2011; 17(19):5256-60. · 5.93 Impact Factor
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ABSTRACT: Using the example of cathepsin K, we demonstrate the design of highly potent and selective azadipeptide nitrile inhibitors. A systematic scan with respect to P2 and P3 substituents was carried out. Structural modifications strongly affected the enzyme-inhibitor association (but not dissociation) rate. A combination of optimized P2 and P3 substituents with a methylation of the P3-P2 amide linker resulted in the picomolar cathepsin K inhibitor 19 with remarkable selectivity over cathepsins L, B, and S.
Journal of Medicinal Chemistry 12/2010; 54(1):396-400. · 4.80 Impact Factor
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ABSTRACT: It is now becoming clear that several papain-like cysteine cathepsins are involved in the pathophysiology of diseases such as osteoporosis, autoimmune disorders, and cancer. Therefore, the development of potent and selective cathepsin inhibitors is an attractive subject for medicinal chemists. New advances have been made for nitrile-based inhibitors, leading to the identification of the cathepsin K inhibitor odanacatib and other candidates with potential for therapeutic use. This review summarizes the development of peptidic and peptidomimetic compounds with an electrophilic nitrile 'warhead' as inhibitors of the cysteine cathepsins B, S, L, C, and K. Peptide nitriles have been shown to reversibly react with the active site cysteine under formation of a covalent thioimidate adduct. The structural optimization with respect to the positions P3, P2, P1, P1', and P2' resulted in the identification of potent and selective inhibitors of the corresponding cathepsins. The underlying structure-activity relationships are discussed herein.
Current topics in medicinal chemistry 02/2010; 10(3):294-322. · 4.47 Impact Factor
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ChemMedChem 12/2009; 5(1):61-4. · 3.15 Impact Factor
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ABSTRACT: Azadipeptide nitriles-novel cysteine protease inhibitors-display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite's hemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of the compounds was observed. These first generation azadipeptide nitriles represent a promising new class of compounds for antimalarial drug development.
Bioorganic & medicinal chemistry letters 10/2009; 20(1):252-5. · 2.65 Impact Factor
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ChemMedChem 01/2009; 4(1):52-4. · 3.15 Impact Factor
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ABSTRACT: The synthesis of a series of new isothiazol-3(2H)-one 1,1-dioxides with halogenated (mostly fluorinated) pyridinyl and pentafluorophenyl substituents at 2-position is reported. These compounds (18-24) became easily accessible from 2-thiocyanato-1-carboxaldehydes and aminopyridines, pentafluoroaniline, respectively, by an isothiazolium cyclization-oxidation route. Compound 21 exhibited an IC(50) value of 3.1 microM toward human leukocyte elastase. The proteases cathepsin G, trypsin, cathepsin L, and angiotensin-converting enzyme, and the serine esterases acetylcholinesterase and cholesterol esterase were not inhibited by 21.
Bioorganic & medicinal chemistry 10/2008; 16(17):8127-35. · 2.82 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(23):4331-4. · 13.45 Impact Factor
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Angewandte Chemie. 01/2008; 120(23):4403-4406.
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ABSTRACT: Modifications of the Zwikker- and Parri color detection tests were examined and compared according to their ability to distinguish between nine different barbituric acids and hydantoins. These tests comprised the formation of complexes with cobalt(II) and copper(II) salts and organic amines. Using the color palette introduced herein, the evaluation of the tests could be reduced to a simple yes/no decision on the basis of only seven defined colors. Suitable components for the color tests could be selected from the thirty six modifications.
Analytical Sciences 01/2006; 21(12):1561-4. · 1.25 Impact Factor
