- The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K
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Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation (kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.
- Mons, Elma,Jansen, Ineke D. C.,Loboda, Jure,Van Doodewaerd, Bjorn R.,Hermans, Jill,Verdoes, Martijn,Van Boeckel, Constant A. A.,Van Veelen, Peter A.,Turk, Boris,Ovaa, Huib
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Read Online
- Discovery of Novel Inhibitors of LpxC Displaying Potent in Vitro Activity against Gram-Negative Bacteria
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UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones, and (iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as 18d, are discussed.
- Surivet, Jean-Philippe,Panchaud, Philippe,Specklin, Jean-Luc,Diethelm, Stefan,Blumstein, Anne-Catherine,Gauvin, Jean-Christophe,Jacob, Lo?c,Masse, Florence,Mathieu, Ga?lle,Mirre, Azely,Schmitt, Christine,Lange, Roland,Tidten-Luksch, Naomi,Gnerre, Carmela,Seeland, Swen,Herrmann, Charlyse,Seiler, Peter,Enderlin-Paput, Michel,Mac Sweeney, Aengus,Wicki, Micha,Hubschwerlen, Christian,Ritz, Daniel,Rueedi, Georg
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supporting information
p. 66 - 87
(2020/01/09)
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- CATHEPSIN INHIBITORS
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This invention relates to compounds that are useful as inhibitors, in particular as inhibitors of Cathepsin K (CatK), and to a method of inhibiting cathepsin activity, comprising administering a compound or formulation comprising a compound according to the invention.
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Paragraph 00136
(2019/06/23)
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- CYCLOPROPYL UREA FORMYL PEPTIDE 2 RECEPTOR AND FORMYL PEPTIDE 1 RECEPTOR AGONISTS
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The disclosure relates to compounds of formula (I), which are formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPRl) receptor agonists. The disclosure also provides compositions and methods of using the compounds, for example, for the tr
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Page/Page column 39
(2019/01/06)
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- ANTIBACTERIAL ANNULATED PYRROLIDIN-2-ONE DERIVATIVES
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The invention relates to antibacterial compounds of formula I wherein X represents sulphur or CH=CH; R1 represents H, PO3H2, SO3H, phosphonooxymethyl or the group -CO-R2 wherein R2 is as defined in the claims M is one of the groups MA and MB represented below wherein A represents a bond or C≡C and R1A, R2A, R3A and R1B are as defined in the claims; and to salts thereof.
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Page/Page column 78
(2017/03/21)
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- ANTIBACTERIAL HETEROCYCLIC DERIVATIVES
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The invention relates to antibacterial compounds of formula (I), wherein R1, M, R2, R3, and V are as described in the description, to their preparation, to salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as antibacterial agents.
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Page/Page column 60
(2017/03/21)
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- SUBSTITUTED 1,2-DIHYDRO-3H-PYRROLO[1,2-C]IMIDAZOL-3-ONE ANTIBACTERIAL COMPOUNDS
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The invention relates to antibacterial compounds of formula (I) wherein M is one of the groups MA, MB and MC represented below wherein R1, MA, MB and MC are as defined in the specification; and to salts thereof.
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Page/Page column 90
(2017/03/21)
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- SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
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Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
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Page/Page column 717; 718
(2016/04/10)
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- Technological synthesis method of 1-amino cyclopropyl acetylene
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The invention discloses a technological synthesis method of 1-amino cyclopropyl acetylene. The method includes: taking compound 1 as the starting material, and carrying out oxidation, Corey-Fuchs reaction, and amino protection group removal so as to obtain the 1-amino cyclopropyl acetylene. The reagents and raw materials used by the method provided by the invention are cheap and easily available, and low in cost. With the advantages of high reaction safety, simple operation and high yield, the method is suitable for industrial scale-up production. (with the synthesis process shown as the specification).
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Paragraph 0040; 0041; 0042; 0043
(2016/10/09)
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- TREATMENT OF DRY EYE
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The present disclosure provides a method of treating dry eye by inhibition of Bruton's tyrosine kinase (hereinafter "BTK") inhibitors, pharmaceutical formulations comprising the same, and processes for preparing such compounds.
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Page/Page column 114; 115
(2014/02/16)
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- Tyrosine kinase inhibitors
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The present disclosure provides compounds such as pyrazolpyrimidine compounds, and pharmaceutically acceptable salts thereof, that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.
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Page/Page column 260
(2014/03/26)
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- REVERSIBLE COVALENT PYRROLO- OR PYRAZOLOPYRIMIDINES USEFUL FOR THE TREATMENT CANCER AND AUTOIMMUNE DISEASES
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Oral pharmaceutical formulations comprising reversible covalent compounds having a Michael acceptor moiety, a process of their production, and use of these formulations for the treatment of diseases treatable by such compounds such as cancer and autoimmune diseases.
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Page/Page column 200
(2014/01/09)
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- TYROSINE KINASE INHIBITORS
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The present disclosure provides compounds and pharmaceutically acceptable salts thereof that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.
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Page/Page column 236
(2012/12/13)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (Formula (I)), including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3, Z1 and Z2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 84
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have one of the following structures (I) or (II): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3 and Z1 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 109
(2011/04/26)
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- Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups
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Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P1 had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P1 group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir.
- Venkatraman, Srikanth,Velazquez, Francisco,Wu, Wanli,Blackman, Melissa,Madison, Vincent,Njoroge, F. George
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scheme or table
p. 2151 - 2155
(2010/06/19)
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- TREATMENT OF URINARY TRACT INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS
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A method for treating a urinary tract infection in a mammal in need thereof is disclosed, the method comprising administering to the mammal an effective amount of an antibacterial aminoglycoside compound.
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Page/Page column 216
(2010/12/17)
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- ORGANIC COMPOUNDS FOR APPLICATIONS IN BACTERIAL INFECTIONS TREATMENT
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The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of human diseases.
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Page/Page column 41
(2010/04/25)
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- DERIVATIVES OF 6,7-DIHYDRO-5H-IMIDAZO[1,2-α]IMIDAZOLE-3- CARBOXYLIC ACID AMIDES
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Derivatives of 6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid amide exhibit good inhibitory effect upon the interaction of CAMs and Leukointegrins and are thus useful in the treatment of inflammatory disease.
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Page/Page column 124-125
(2009/07/03)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds of structure (I): having antibacterial activity are disclosed, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R8 and R9 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 207
(2009/06/27)
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- ALPHA KETOAMIDE COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
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- ALPHA KETOAMIDE COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
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Page/Page column 60
(2008/06/13)
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- Chemokine receptor binding heterocyclic compounds with enhanced efficacy
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The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
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- Chemokine receptor binding heterocyclic compounds with enhanced efficacy
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The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
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Page/Page column 49-50
(2010/02/03)
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- Acyl sulfonamides as potent protease inhibitors of the hepatitis C virus full-length NS3 (protease-helicase/NTPase): A comparative study of different C-terminals
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Synthesis and inhibitory potencies of three types of protease inhibitors of the hepatitis C virus (HCV) full-length NS3 (protease-helicase/NTPase) are reported: (i) inhibitors comprising electrophilic serine traps (pentafluoroethyl ketones, α-keto acids,
- Johansson, Anja,Poliakov, Anton,Akerblom, Eva,Wiklund, Karin,Lindeberg, Gunnar,Winiwarter, Susanne,Danielson, U. Helena,Samuelsson, Bertil,Hallberg, Anders
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p. 2551 - 2568
(2007/10/03)
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- Synthesis and structure-activity relationships of 7-[3-(1- aminoalkyl)pyrrolidinyl]- and 7-[3-1-aminocycloalkyl)pyrrolidinyl]-quinolone antibacterials
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A series of 7-[3-(1-aminoalkyl and 1-aminocycloalkyl)-1- pyrrolidinyl]quinolones have been prepared and their biological properties evaluated. Among them, 1-(S)-aminoalkyl derivatives exhibited potent antibacterial activities against gram-positive and gram-negative organisms. They had moderate lipophilicity and high aqueous solubility compared to their aminomethyl counterparts; e.g., the 3-(1-aminoethyl)-1-pyrrolidinyl compound (83) showed superior pharmacokinetic properties to its aminomethyl counterpart (6).
- Kimura,Atarashi,Takahashi,Hayakawa
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p. 1442 - 1454
(2007/10/02)
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- Pyridonecarboxylic acid derivatives
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This invention provides novel pyridonecarboxylic acid derivatives having a quite high antimicrobial activity. The derivatives have the following formula: STR1 wherein R1, R2 and R3 represent each a hydrogen or C1 -C6 alkyl group; R4 represents an ethyl, 2-fluoroethyl, vinyl, isopropyl, isopropenyl or cyclopropyl group; and X represents CH, C-F, C-Cl or N wherein (i) one of R1, R2 and R3 represents a hydrogen or C1 -C6 alkyl group, and (ii) either R1 forms a methylene chain having 2 to 4 carbon atoms together with R2 or R3, or R2 and R3 form together an alkylene chain having 2 to 5 atoms and R4 represents an ethyl, 2-fluorethyl, vinyl, isopropyl, isopropenyl or cyclopropyl group and X represents CH, C-F, or C-Cl and salt thereof.
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- Synthesis of a novel tricyclic 4-quinolone. Incorporation of a spiro-cyclopropyl group at N1 by bridging to C2
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An important pharmacophore in many quinolone antiinfectives is the N1 cyclopropane. By incorporating the cyclopropane into a N1 to C2 bridge, the first quinolone substrate incorporating a spiro fused cyclopropane, 8,9,10-trifluoro-2,3,4,6-tetrahydro-6-oxo
- Schroeder,Kiely
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p. 1769 - 1772
(2007/10/02)
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- L-aminodicarboxylic acid alkenes
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This invention relates to new novel sweeteners of the formula: STR1 wherein A is hydrogen, alkyl containing 1-3 carbon atoms or alkoxymethyl wherein the alkoxy contains 1-3 carbon atoms; A' is hydrogen or alkyl containing 1-3 carbon atoms; A and A' taken together with the carbon atom to which they are attached form cycloalkyl containing 3-4 carbon atoms; Y is --(CHR2)n --R1, --CHR3 R4 or R5 ; R1 is cycloalkyl, cycloalkenyl, bicycloalkyl or bicycloalkenyl containing up to 7 ring carbon atoms and up to a total of 12 carbon atoms; R5 is alkyl containing up to 11 carbon atoms; R2 is H or alkyl containing 1-4 carbon atoms; R3 and R4 are each cycloalkyl containing 3-4 ring carbon atoms; n=0 or 1; and m=0 or 1; and food-acceptable salts thereof.
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