Cathepsin S inhibitors: 2004 – 2010

Introduction: Cathepsin S, a lysosomal cysteine protease, plays an important role in antigen presentation. Its inhibition is expected to result in immunosuppression, making this enzyme an attractive target to potentially treat autoimmune and inflammatory diseases. Areas covered: The focus of this review is on patent literature regarding small molecule inhibitors of cathepsin S published from 2004 to April 2010. Different structure classes based on binding strategies (covalent vs non-covalent) are surveyed and listed according to warhead type and research organization. Expert opinion: Although > 40 patent applications have appeared between 2004 and 2010, the decrease in applications focusing on cathepsin S over the past 2 – 3 years may reflect a renewed interest in other cathepsins, especially cathepsin K, for which a small molecule inhibitor is currently in Phase III clinical trials.

[1]  Jun Li,et al.  Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers. , 2006, Bioorganic & medicinal chemistry letters.

[2]  John J. M. Wiener,et al.  Recent advances in the design of cathepsin S inhibitors. , 2010, Current topics in medicinal chemistry.

[3]  Makoto Naito,et al.  Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. , 2003, The Journal of clinical investigation.

[4]  S. Bevan,et al.  Discovery of orally bioavailable cathepsin S inhibitors for the reversal of neuropathic pain. , 2008, Journal of medicinal chemistry.

[5]  James P Edwards,et al.  Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements. , 2009, Bioorganic & medicinal chemistry letters.

[6]  Jean-François Truchon,et al.  A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds. , 2007, Bioorganic & medicinal chemistry letters.

[7]  B. Maryanoff,et al.  Inhibitors of proteases and amide hydrolases that employ an alpha-ketoheterocycle as a key enabling functionality. , 2008, Bioorganic & medicinal chemistry.

[8]  M. Percival,et al.  The identification of potent, selective, and bioavailable cathepsin S inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[9]  R. Mitchell,et al.  Cathepsin S activity regulates antigen presentation and immunity. , 1998, The Journal of clinical investigation.

[10]  X. Fradera,et al.  Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[11]  J. Link,et al.  Advances in cathepsin S inhibitor design. , 2006, Current opinion in drug discovery & development.

[12]  S. Bevan,et al.  Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain , 2007, Proceedings of the National Academy of Sciences.

[13]  S. Steinbacher,et al.  Design of selective Cathepsin inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[14]  J. Falgueyret,et al.  The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. , 2008, Bioorganic & medicinal chemistry letters.

[15]  R. Kalluri,et al.  Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors* , 2006, Journal of Biological Chemistry.

[16]  John J. Peterson,et al.  Inhibition of Invariant Chain Processing, Antigen-Induced Proliferative Responses, and the Development of Collagen-Induced Arthritis and Experimental Autoimmune Encephalomyelitis by a Small Molecule Cysteine Protease Inhibitor , 2008, The Journal of Immunology.

[17]  Jennifer L. Harris,et al.  Arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 2: Optimization of P1 and N-aryl. , 2006, Bioorganic & Medicinal Chemistry Letters.

[18]  E. Altmann,et al.  2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K. , 2007, Journal of medicinal chemistry.

[19]  John J. M. Wiener,et al.  Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions. , 2010, Bioorganic & medicinal chemistry letters.

[20]  Jun Li,et al.  Arylaminoethyl carbamates as a novel series of potent and selective cathepsin S inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[21]  R. Thurmond,et al.  Cathepsin S inhibitors as novel immunomodulators. , 2005, Current opinion in investigational drugs.

[22]  W. Jahnke,et al.  Arylaminoethyl amides as novel non-covalent cathepsin K inhibitors. , 2002, Journal of medicinal chemistry.

[23]  D. Teupser,et al.  Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  T. Kanazawa,et al.  Discovery of selective and nonpeptidic cathepsin S inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[25]  P. Libby,et al.  Deficiency of the Cysteine Protease Cathepsin S Impairs Microvessel Growth , 2003, Circulation research.

[26]  James P Edwards,et al.  Thioether acetamides as P3 binding elements for tetrahydropyrido-pyrazole cathepsin S inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[27]  J. Palmer,et al.  Cysteine protease activity is up-regulated in inflamed ankle joints of rats with adjuvant-induced arthritis and decreases with in vivo administration of a vinyl sulfone cysteine protease inhibitor. , 2001, Arthritis and rheumatism.

[28]  Joost C. M. Uitdehaag,et al.  6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[29]  A. Rudensky,et al.  Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. , 1999, Immunity.

[30]  Soraya S. Porres,et al.  5-Aminopyrimidin-2-ylnitriles as cathepsin K inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[31]  L. Holsinger,et al.  Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model. , 2010, Biochimie.

[32]  T. Kanazawa,et al.  4-Amino-2-cyanopyrimidines: novel scaffold for nonpeptidic cathepsin S inhibitors. , 2008, Bioorganic & Medicinal Chemistry Letters.

[33]  Scott Lesley,et al.  Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method. , 2006, Journal of medicinal chemistry.

[34]  Jennifer L. Harris,et al.  Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S. , 2007, Bioorganic & medicinal chemistry letters.

[35]  Jun Li,et al.  Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: heterocyclic P3. , 2006, Bioorganic & medicinal chemistry letters.

[36]  B. Samuelsson,et al.  Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: effect of sulfonamides P3 substituents on potency and selectivity. , 2009, Bioorganic & medicinal chemistry.

[37]  J. Falgueyret,et al.  Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. , 2005, Journal of medicinal chemistry.

[38]  X. Fradera,et al.  4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important. , 2010, Bioorganic & medicinal chemistry letters.

[39]  Traian Sulea,et al.  Specificity determinants of human cathepsin s revealed by crystal structures of complexes. , 2003, Biochemistry.

[40]  S. Bevan,et al.  Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2. , 2008, Bioorganic & medicinal chemistry letters.

[41]  Hwan-Moon Song,et al.  Simple fabrication of functionalized surface with polyethylene glycol microstructure and glycidyl methacrylate moiety for the selective immobilization of proteins and cells , 2008 .

[42]  A. Ray,et al.  Cysteine cathepsin S as an immunomodulatory target: present and future trends , 2008, Expert opinion on therapeutic targets.

[43]  J. Ellman,et al.  Substrate activity screening: a fragment-based method for the rapid identification of nonpeptidic protease inhibitors. , 2005, Journal of the American Chemical Society.

[44]  X. Fradera,et al.  2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[45]  Cheryl A. Grice,et al.  Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1. , 2010, Bioorganic & medicinal chemistry letters.

[46]  E. Altmann,et al.  Arylaminoethyl amides as inhibitors of the cysteine protease cathepsin K-investigating P1' substituents. , 2003, Bioorganic & medicinal chemistry letters.

[47]  James P Edwards,et al.  Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[48]  J. Ellman,et al.  Substrate activity screening (SAS): a general procedure for the preparation and screening of a fragment-based non-peptidic protease substrate library for inhibitor discovery , 2007, Nature Protocols.

[49]  S. Steinbacher,et al.  Dipeptidyl nitrile inhibitors of Cathepsin L. , 2009, Bioorganic & medicinal chemistry letters.

[50]  G. Dranoff,et al.  Cathepsin S required for normal MHC class II peptide loading and germinal center development. , 1999, Immunity.

[51]  Vincent Leroy,et al.  Cathepsin S inhibitors , 2004 .

[52]  O. Ohmori,et al.  Novel scaffold for cathepsin K inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[53]  Jennifer L. Harris,et al.  Design and synthesis of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 1. , 2005, Bioorganic & medicinal chemistry letters.

[54]  James P Edwards,et al.  Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: optimization of cellular potency. , 2009, Bioorganic & medicinal chemistry letters.

[55]  O. Vasiljeva,et al.  Emerging roles of cysteine cathepsins in disease and their potential as drug targets. , 2007, Current pharmaceutical design.