- The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection
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The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
- Scola, Paul M.,Sun, Li-Qiang,Wang, Alan Xiangdong,Chen, Jie,Sin, Ny,Venables, Brian L.,Sit, Sing-Yuen,Chen, Yan,Cocuzza, Anthony,Bilder, Donna M.,D'Andrea, Stanley V.,Zheng, Barbara,Hewawasam, Piyasena,Tu, Yong,Friborg, Jacques,Falk, Paul,Hernandez, Dennis,Levine, Steven,Chen, Chaoqun,Yu, Fei,Sheaffer, Amy K.,Zhai, Guangzhi,Barry, Diana,Knipe, Jay O.,Han, Yong-Hae,Schartman, Richard,Donoso, Maria,Mosure, Kathy,Sinz, Michael W.,Zvyaga, Tatyana,Good, Andrew C.,Rajamani, Ramkumar,Kish, Kevin,Tredup, Jeffrey,Klei, Herbert E.,Gao, Qi,Mueller, Luciano,Colonno, Richard J.,Grasela, Dennis M.,Adams, Stephen P.,Loy, James,Levesque, Paul C.,Sun, Huabin,Shi, Hong,Sun, Lucy,Warner, William,Li, Danshi,Zhu, Jialong,Meanwell, Nicholas A.,McPhee, Fiona
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Read Online
- Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization
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A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.
- Jaime-Figueroa, Saul,Bond, Michael J.,Vergara, J. Ignacio,Swartzel, Jake C.,Crews, Craig M.
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p. 8479 - 8488
(2021/06/28)
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- GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with a defect in glyoxylate metabolism, for example a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
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Paragraph 00950; 00951
(2021/01/22)
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- GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO). Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
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Paragraph 00992; 00993; 00995
(2019/07/17)
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- Process for Synthesizing Substituted Isoquinolines
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The present disclosure generally relates to a process for synthesizing optionally substituted 1-chloro-4-methoxyisoquinolines. The present disclosure also relates to intermediates useful in this process.
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Page/Page column 6
(2010/04/23)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 36
(2009/12/02)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 15-16
(2009/12/05)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 139
(2008/12/05)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula:(I) wherein R1, R2, R3, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds toinhibit HCV are also disclosed.
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- Synthesis of novel substituted isoquinolones
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A series of novel substituted isoquinolones have been synthesised. This has been achieved by two routes, either Curtius rearrangment of cinnamic acids or via an isoquinoline N-oxide.
- Briet, Nicolas,Brookes, Michael H,Davenport, Richard J,Galvin, Frances C.A,Gilbert, Philip J,Mack, Stephen R,Sabin, Verity
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p. 5761 - 5766
(2007/10/03)
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- Palladium-catalyzed Synthesis of Isocoumarin and 1-Isoquinolinone Derivatives
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In the presence of copper(I) chloride, the palladium catalyzed oxidation of methyl 2-ethenylbenzoates and 2-ethenylbenzamides have been studied.This reaction was used to form isocoumarins and 1-isoquinolinones.
- Izumi, Taeko,Nishimoto, Yasuhiro,Kohei, Kunihiro,Kasahara, Akira
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p. 1419 - 1424
(2007/10/02)
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- 78. Tricyclic pyridine derivatives with high affinity to the central benzodiazepine receptor
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Novel tricyclic heterocycles were prepared and evaluated for their affinity to the central benzodiazepine receptor. The most potent compounds with IC50's in the nanomolar range were found among thienoquinolizines and benzo[a]quinolizines (cf. Tables 2-5). The central ring of the tricyclic ring system may be partially unsaturated (cf. Tables 2 and 4) or fully unsaturated (cf. Tables 3 and 5) without loss of the high affinity to the receptor. The position of the ester group in the pyridinone ring is crucial for good binding (cf. Tables 1 and 2). It may be replaced by a broad variety of functional groups, e.g., amides, alkyl carbamates, alkyl groups, and hydroxyalkyl groups (cf. Tables 2-5). In the benzo[a]quinolizines, shifting the halogen atom from C(10) to C(9) leads to complete loss of affinity to the benzodiazepine receptor (cf. Table 4).
- Fischer,Mohler,Schneider,Widmer
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p. 763 - 781
(2007/10/02)
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