- Development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors: Biological evaluation and structural characterization by cocrystallization
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Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use, including the artemisinin-based combinations, which are the last line of defense against malaria. This necessitates the discovery of new targets and the development of novel antimalarials. Plasmodium falciparum alanyl aminopeptidase (PfA-M1) and leucyl aminopeptidase (PfA-M17) belong to the M1 and M17 family of metalloproteases respectively and play critical roles in the asexual erythrocytic stage of development. These enzymes have been suggested as potential antimalarial drug targets. Herein we describe the development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors. Most of the compounds described in this study display inhibition at sub-micromolar range against the recombinant PfA-M1 and PfA-M17. More importantly, compound 26 not only exhibits potent malarial aminopeptidases inhibitory activities (PfA-M1 Ki = 0.11 ± 0.0002 μmol/L, PfA-M17 Ki = 0.05 ± 0.005 μmol/L), but also possesses remarkable selectivity over the mammalian counterpart (pAPN Ki = 17.24 ± 0.08 μmol/L), which endows 26 with strong inhibition of the malarial parasite growth and negligible cytotoxicity on human cell lines. Crystal structures of PfA-M1 at atomic resolution in complex with four different compounds including compound 26 establish the structural basis for their inhibitory activities. Notably, the terminal ureidobenzyl group of 26 explores the S2′ region where differences between the malarial and mammalian enzymes are apparent, which rationalizes the selectivity of 26. Together, our data provide important insights for the rational and structure-based design of selective and dual inhibitors of malarial aminopeptidases that will likely lead to novel chemotherapeutics for the treatment of malaria.
- Addlagatta, Anthony,Ding, Yongzheng,Ma, Chunhua,Marapaka, Anil Kumar,Pillalamarri, Vijaykumar,Reddi, Bharati,Sankoju, Priyanka,Sijwali, Puran Singh,Sudhakar, Renu,Zhang, Guozhen,Zhang, Yingjie
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supporting information
(2021/12/01)
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- A PROCESS FOR THE PREPARATION OF SUBSTITUTED PROLYL PEPTIDES AND SIMILAR PEPTIDOMIMETICS
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The present invention relates to a process for the stereoselective preparation of a compound having the general formula (I) or its respective diastereomers: comprising reacting a compound having the general formula (II) or its diastereomers: with a compound of the general formula III: R3-COOH and a compound of the general formula IV: R4-NC wherein R1 represents each independently, or jointly a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R2 represents a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R3 represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure.
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Page/Page column 42; 43
(2011/09/21)
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- Chemical and biological evaluation of dipeptidyl boronic acid proteasome inhibitors for use in prodrugs and pro-soft drugs targeting solid tumors
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Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S proteasome, is remarkably effective against multiple myeloma (MM) but not against solid tumors. Dose-limiting adverse effects from "on target" inhibition of the proteasome in normal cells and tissues appear to be a key obstacle. Achieving efficacy against solid tumors therefore is likely to require making the inhibitor more selective for tumor tissue over normal tissues. The simplest strategy that might provide such tissue specificity would be to employ a tumor specific protease to release an inhibitor from a larger, noninhibitory structure. However, such release would necessarily generate an inhibitor with a free N-terminal amino group, raising a key question: Can short peptide boronic acids with N-terminal amino groups have the requisite properties to serve as warheads in prodrugs? Here we show that dipeptides of boroLeu, the smallest plausible candidates for the task, can indeed be sufficiently potent, cell-penetrating, cytotoxic, and stable to degradation by cellular peptidases to serve in this capacity.
- Milo, Lawrence J.,Lai, Jack H.,Wu, Wengen,Liu, Yuxin,Maw, Hlaing,Li, Youhua,Jin, Zhiping,Shu, Ying,Poplawski, Sarah E.,Wu, Yong,Sanford, David G.,Sudmeier, James L.,Bachovchin, William W.
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experimental part
p. 4365 - 4377
(2011/09/15)
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- A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions
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A very short and efficient synthesis of the important drug candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective groups.
- Znabet, Anass,Polak, Marloes M.,Janssen, Elwin,De Kanter, Frans J. J.,Turner, Nicholas J.,Orru, Romano V. A.,Ruijter, Eelco
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supporting information; experimental part
p. 7918 - 7920
(2010/12/19)
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- HCV PROTEASE INHIBITORS AND USES THEREOF
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This invention relates to: (a) compounds of formula I and salts thereof that, inter alia, are useful as hepatitis C virus (HCV) inhibitors; (b) intermediates useful for the preparation of such compounds and salts; (c) pharmaceutical compositions comprising such compounds and salts; and (d) methods of use of such compounds, salts, and compositions.
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Page/Page column 20
(2010/03/02)
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- HCV PROTEASE INHIBITORS AND USES THEREOF
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Page/Page column 57
(2010/03/04)
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- Pharmaceutical formulations and methods of treatment using the same
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Pharmaceutical formulations containing at least one compound of Formulae I-XXVI herein and at least one surfactant. Pharmaceutically acceptable carriers and excipients may also be included in the formulations. The formulations of the present invention are suited for use in single unit dosages.
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Page/Page column 436
(2010/11/25)
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- Liver/plasma concentration ratio for dosing hepatitis C virus protease inhibitor
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Compositions and therapeutic combinations are provided including at least one compound selected from the group consisting of compounds of Formulae I to XXVI as defined herein as well as methods of treatment, prevention or amelioration of one or more symptoms of hepatitis C, treating disorders associated with HCV virus, modulating activity of HCV protease, in which liver to plasma concentration ratio of the compound ranges from about 2:1 to about 10:1.
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Page/Page column 500
(2010/11/25)
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- ORGANIC COMPOUNDS AND THEIR USES
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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 89-90
(2010/11/28)
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- Controlled-release formulation
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Controlled-release dosage formulations including at least one compound of Formulae I to XXVI herein and a controlled-release carrier and methods of treatment using the same are provided.
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Page/Page column 432-433
(2010/11/25)
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- Methods for treating hepatitis C
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Methods of treating hepatitis C are provided comprising using a therapeutically effective amount of at least one novel hepatitis C (“HCV”) protease inhibitor or, alternatively, at least one antiviral or immuno-modulating HCV agent, which is not an HCV protease inhibitor, for a first treatment period. Subsequently, a combination of the at least one novel hepatitis C (“HCV”) protease inhibitor and the at least one antiviral or immuno-modulating HCV agent are administered in a therapeutically effective amount for a second treatment period. The methods are provided for treating a wide variety of diseases, disorders and symptoms associated with hepatitis C virus by modulating the activity of HCV protease (for example HCV NS3/NS4a serine protease) in a subject.
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Page/Page column 537-538
(2010/11/25)
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- Methods of treating hepatitis C virus
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Compositions and therapeutic combinations are provided including at least one compound selected from the group consisting of compounds of Formulae I to XXVI as defined herein as well as methods of treatment, prevention or amelioration of one or more symptoms of hepatitis C, treating disorders associated with HCV virus, modulating activity of HCV protease, or inhibiting cathepsin activity in a subject using the same, in which the mean volume of distribution/bioavailability (Vd/F) of the compound as measured in the plasma of the subject is greater than about 1000 L.
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Page/Page column 397
(2010/11/25)
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- Medicaments and methods combining a HCV protease inhibitor and an AKR competitor
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Disclosed are medicaments, pharmaceutical compositions, pharmaceutical kits, and methods based on combinations of a hepatitis C virus (HCV) protease inhibitor and an aldo-keto reductase (AKR) competitor, for concurrent or consecutive administration in treating, preventing, or ameliorating one or more symptoms of HCV, treating disorders associated with HCV, or inhibiting cathepsin activity in a subject.
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Page/Page column 62
(2010/11/25)
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- Administration of HCV protease inhibitors in combination with food to improve bioavailability
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Methods of treating, preventing or ameliorating one or more symptoms of hepatitis C in a subject comprising the step of administering at least one HCV protease inhibitor in combination with food are provided. Also provided are methods of increasing bioavailability of an HCV protease inhibitor and methods of increasing serum levels of an HCV protease inhibitor in a subject. All methods comprise adminstering at least one HCV protease inhibitor in combination with food, the at least one HCV protease inhibitor selected from the group consisting of compounds of Formulae I-XXVI, described herein. Administration of compounds of the present invention in combination with food provides improved bioavailability and increased peak serum levels of the compounds as compared to administration without food.
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Page/Page column 609
(2010/11/25)
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- METHOD FOR MODULATING ACTIVITY OF HCV PROTEASE THROUGH USE OF A NOVEL HCV PROTEASE INHIBITOR TO REDUCE DURATION OF TREATMENT PERIOD
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Methods are provided for using at least one novel hepatitis C ("HCV") protease inhibitor in combination with at least one antiviral and/or immunomodulatory agent, which is different from the at least one HCV protease inhibitor, for treating a wide variety of diseases or disorders associated with hepatitis C virus by modulating the activity of HCV protease (for example HCV NS3/NS4a serine protease) and reducing HCV viral load in a subject in a reduced treatment period. With the present invention, a hepatitis C viral load is reduced in a subject to a concentration of less than 6?10-5 HCV virions per milliliter of plasma in a time period of less than or equal to about 24 weeks. With the present invention, a hepatitis C viral production is suppressed with an effectiveness in a range of 0.7 to 0.997. "
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Page/Page column 514
(2010/11/25)
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- METHOD OF TREATING INTERFERON NON-RESPONDERS USING HCV PROTEASE INHIBITOR
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A method of treating, preventing or ameliorating one or more symptoms associated with hepatitis C virus (HCV) in a patient in whom either the HCV is of Genotype 1 and/or the patient was previously treated with interferon and the previous interferon therapy was ineffective to treat the one or more symptoms associated with HCV, comprising administering to such a patient an effective amount of at least one compound of formulae I-XXVI of which the structural formula (I) is exemplary or a pharmaceutically acceptable salt, solvate or ester thereof. Optional combined administration of said at least one compound with an interferon or pegylated interferon and/or ribaviron is also contemplated.
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Page/Page column 380
(2010/11/25)
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- ASYMMETRIC DOSING METHODS
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A method of treating, preventing or ameliorating one or more symptoms of hepatitis C, or inhibiting cathepsin activity, in a subject is provided, in which at least one compound (e.g., a HCV protease inhibitor) is administered in one or more discrete dosages over a twenty-four hour time interval in an asymmetric pattern as to dosage amount and/or timing of dosage, wherein the at least one compound is selected from the group consisting of compounds of Formulae I-XXVI, described herein. Methods of modulating the activity of hepatitis C virus protease in a subject are also provided. Asymmetric dosing as to amount of dose and/or timing of dose permits adjustment of dosing to accommodate variations in drug metabolism and/or viral activity caused by viral cell division or a patient's circadian rhythms, thus delivering the maximum amount of dose at the time or times it is most effective.
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Page/Page column 416
(2010/11/25)
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- Methods of treating hepatitis C virus
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Methods for preventing, ameliorating or treating one or more symptoms of Hepatitis C virus (HCV), modulating HCV protease activity and/or inhibiting cathepsin activity in a subject, wherein the methods comprise administering to a subject in need of such treatment a dosage formulation containing at least one compound of Formulae I-XXVI herein, wherein the dosage formulation is capable of maintaining an average Cmin plasma concentration of the compound at or above 10 ng/ml.
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Page/Page column 453-454
(2008/06/13)
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- INHIBITORS OF HEPATITIS C VIRUS NS3/NS4A SERINE PROTEASE
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The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as me
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Page/Page column 56-57
(2008/06/13)
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