- Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy
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Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.
- Banerjee, Abhisek,Behera, Dayanidhi B.,Chakraborti, Samitabh,Das, Sanjib,Gharat, Laxmikant A.,Iyer, Pravin S.,Kadam, Pradip,Karanjai, Keya,Patil, Sandip,Pawar, Mahesh,Qadri, Mohammad Mohsin,Saini, Jagmohan S.,Velagaleti, Ranganadh,Yadav, Pravin
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- SUBSTITUTED BICYCLIC 1-CARBOXYLIC-ACID (BENZYL-CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C
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This invention relates to bicyclic 1-carboxylic-acid (benzyl-cyano-methyl)-amides of formula 1 and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and their use in methods of treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.
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Page/Page column 73
(2014/09/29)
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- SUBSTITUTED 2-AZA-BICYCLO[2.2.2]OCTANE-3-CARBOXYLIC ACID (BENZYL-CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C
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This invention relates to 2-Aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1 and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.
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Paragraph 0311; 0312
(2014/09/30)
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- SUBSTITUTED 2-AZA-BICYCLO[2.2.2]OCTANE-3-CARBOXYLIC ACID (BENZYL-CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C
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This invention relates to 2-Aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1 and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. asthma and allergic diseases, gastrointestinal inflammatory diseases, eosinophilic diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes, rheumatoid arthritis or atherosclerosis.
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Page/Page column 68; 69; 70
(2014/09/29)
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- SUBSTITUTED BICYCLIC 1-CARBOXYLIC-ACID (BENZYL-CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C
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This invention relates to bicyclic 1-carboxylic-acid (benzyl-cyano-methyl)-amides of formula 1 and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.
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Paragraph 0318; 0319
(2014/09/30)
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- Cathepsin C inhibitors: Property optimization and identification of a clinical candidate
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A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.
- Furber, Mark,Tiden, Anna-Karin,Gardiner, Philip,Mete, Antonio,Ford, Rhonan,Millichip, Ian,Stein, Linda,Mather, Andrew,Kinchin, Elizabeth,Luckhurst, Christopher,Barber, Simon,Cage, Peter,Sanganee, Hitesh,Austin, Rupert,Chohan, Kamaldeep,Beri, Raj,Thong, Bob,Wallace, Alan,Oreffo, Victor,Hutchinson, Ray,Harper, Steve,Debreczeni, Judit,Breed, Jason,Wissler, Lisa,Edman, Karl
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p. 2357 - 2367
(2014/04/17)
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- SUBSTITUTED N- [1-CYANO-2- (PHENYL) ETHYL] -2-AZABICYCLO [2.2.1] HEPTANE-3-CARBOXAMIDE INHIBITORS OF CATHEPSIN C
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This invention relates to N-1-cyano-2-(phenyl)ethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamides of formula I, and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of respiratory diseases.
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Page/Page column 33
(2013/04/10)
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- SUBSTITUTED N- [1-CYANO-2- (PHENYL) ETHYL] -2-AZABICYCLO [2.2.1] HEPTANE-3-CARBOXAMIDE INHIBITORS OF CATHEPSIN C
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Disclosed are N-1-cyano-2-(phenyl)ethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamides of formula I and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of respiratory diseases.
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Paragraph 0179
(2013/07/19)
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- SUBSTITUTED N-[1-CYANO-2-(PHENYL)ETHYL] 1-AMINOCYCLOALK-1-YLCARBOXAMIDE COMPOUNDS - 760
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The present invention provides compounds of formula (I) in which, n, R1, R2 and Q are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 49-50
(2012/01/05)
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- SUBSTITUTED 1-CYANOETHYLHETEROCYCLYLCARBOXAMIDE COMPOUNDS 750
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The present invention provides compounds of formula (I), in which y, m, n, R1, R2 and Q are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 42; 50
(2010/11/18)
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- SUBSTITUTED N-[1-CYANO-2-(PHENYL)ETHYL]PIPERIDIN-2-YLCARBOXMIDE COMPOUNDS 761
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The present invention provides a compound: (S)-N-((S)-1-Cyano-2-(4-(1-methyl-2-oxoindolin-6-yl)phenyl)ethyl)piperidine-2- carboxamide; (S)-N-((S)-1-Cyano-2-(4-(3-(3-methoxypropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)piperidine-2-carboxamide; (S)-N-((S)-1-Cyano-2-(4'-(ethylsulfonyl)biphenyl-4-yl)ethyl)piperidine-2-carboxamide; 4'-((S)-2-Cyano-2-((S)-piperidine-2-carboxamido)ethyl)biphenyl-4-yl methanesulfonate; or, (S)-N-((S)-1-Cyano-2-(4-(1-oxoisoindolin-5-yl)phenyl)ethyl)piperidine-2-carboxamide; or a pharmaceutically acceptable salt thereof; a process for its preparation, pharmaceutical compositions containing it and its use in therapy.
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Page/Page column 18-19
(2010/12/29)
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- CYSTEINE PROTEASE INHIBITORS FOR THE TREATMENT OF PARASITIC DISEASES
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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, strongyloidiasis, trichostrongyliasis, trichomoniasis or cestodiasis. Compounds of formula I of the invention are capable of treating and/or preventing the above-identified diseases:
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Page/Page column 43-44
(2009/07/03)
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- PEPTIDYL NITRILES AND USE THEREOF AS DIPEPTIDYL PEPTIDASE I INHIBITORS
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The present invention provides compounds of formula (I) in which n, y, X1, X2, A, B, R1, R2, R3, R4 and R5 are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use as dipeptidyl peptidase I (DPPI) inhibitors.
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Page/Page column 44
(2009/07/17)
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- Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics
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Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
- Combs, Andrew P.,Yue, Eddy W.,Bower, Michael,Ala, Paul J.,Wayland, Brian,Douty, Brent,Takvorian, Amy,Polam, Padmaja,Wasserman, Zelda,Zhu, Wenyu,Crawley, Matthew L.,Pruitt, James,Sparks, Richard,Glass, Brian,Modi, Dilip,McLaughlin, Erin,Bostrom, Lori,Li, Mei,Galya, Laurine,Blom, Karl,Hillman, Milton,Gonneville, Lucie,Reid, Brian G.,Wei, Min,Becker-Pasha, Mary,Klabe, Ronald,Huber, Reid,Li, Yanlong,Hollis, Gregory,Burn, Timothy C.,Wynn, Richard,Liu, Phillip,Metcalf, Brian
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p. 6544 - 6548
(2007/10/03)
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