- Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease
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Flaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there are no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for viral replication and therefore a drug target. Compound screening followed by medicinal chemistry yielded a series of drug-like, broadly active inhibitors of Flavivirus proteases with IC50 as low as 120 nM. The inhibitor exhibited significant antiviral activities in cells (EC68: 300-600 nM) and in a mouse model of Zika virus infection. X-ray studies reveal that the inhibitors bind to an allosteric, mostly hydrophobic pocket of dengue NS3 and hold the protease in an open, catalytically inactive conformation. The inhibitors and their binding structures would be useful for rational drug development targeting Zika, dengue and other Flaviviruses.
- Yao, Yuan,Huo, Tong,Lin, Yi-Lun,Nie, Shenyou,Wu, Fangrui,Hua, Yuanda,Wu, Jingyu,Kneubehl, Alexander R.,Vogt, Megan B.,Rico-Hesse, Rebecca,Song, Yongcheng
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Read Online
- Synthesis of 5-Trifluoromethyl-Substituted (Z)- N, N -Dimethyl- N '-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO 2CF 2CO 2Me and DMF under Cu Catalysis
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The synthesis of 5-trifluoromethyl-substituted (Z)-N,N-dimethyl-N'-(pyrazin-2-yl)formimidamides via the iodination of 2-aminopyrazines with Selectfluor/LiI followed by a domino trifluoromethylation with FSO2CF2CO2Me and a condensation with DMF in the presence of CuI is realized under mild conditions. This three-step method offers CF3-substituted (Z)-N,N-dimethyl-N'-(pyrazin-2-yl)formimidamides in yields of 55 70% and with high regioselectivities. LiI serves as an iodine source, whilst DMF functions as both a solvent and a condensation reagent. The regioselectivity of these trifluoromethylation reactions is strongly dependent upon the substituent pattern on the 2-aminopyrazines. A possible mechanism for this method is also discussed.
- Hu, Jiao,Li, Shengyu,Wang, Xiaolin,Zhao, Xiaoming,Zheng, Sheng-Cai
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- Synthesis, Structure-Activity Relationships, and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease
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Flaviviruses, including Zika, dengue, and West Nile viruses, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screening, followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile viruses, and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus replication in cells with EC68 values of 300-600 nM and in a mouse model of Zika infection. These compounds represent novel pharmacological leads for drug development against Flavivirus infections.
- Nie, Shenyou,Yao, Yuan,Wu, Fangrui,Wu, Xiaowei,Zhao, Jidong,Hua, Yuanda,Wu, Jingyu,Huo, Tong,Lin, Yi-Lun,Kneubehl, Alexander R.,Vogt, Megan B.,Ferreon, Josephine,Rico-Hesse, Rebecca,Song, Yongcheng
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p. 2777 - 2800
(2021/03/09)
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- NOVEL INHIBITORS OF FLAVIVIRUS PROTEASE FOR PREVENTION AND TREATMENT OF ZIKA, DENGUE AND OTHER FLAVIVIRUS INFECTIONS
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In some embodiments, the present disclosure pertains to compositions that inhibit flavivirus proteases. In additional embodiments, the present disclosure pertains to methods for treating a viral infection in a subject by administering the compositions of the present disclosure to the subject. In some embodiments, the viral infection is caused by a flavivirus such as, for example, dengue virus, West Nile virus, Zika virus, tick-bome encephalitis virus, yellow fever virus, viruses causing encephalitis, insect- specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof.
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Paragraph 0053; 0063-0064; 00116-00118
(2020/10/21)
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- HETEROCYCLIC COMPOUNDS AS ADENOSINE ANTAGONISTS
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Aminopyrazine compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.
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Paragraph 0417; 0418
(2019/02/05)
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- PDE9 INHIBITORS FOR TREATMENT OF PERIPHERAL DISEASES
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The present invention relates to PDE9 inhibitors, their synthesis, and their use for treatment of benign prostate hyperplasia, beta thalassemia, and sickle cell disease.
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Paragraph 00195; 00200-00201
(2018/09/25)
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- Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptor
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On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a–c) were synthesized containing a 2-fluoropyridine moiety suitable for 18F-labeling. Compound 7a was docked into a homology model of the A2B
- Lindemann, Marcel,Hinz, Sonja,Deuther-Conrad, Winnie,Namasivayam, Vigneshwaran,Dukic-Stefanovic, Sladjana,Teodoro, Rodrigo,Toussaint, Magali,Kranz, Mathias,Juhl, Cathleen,Steinbach, J?rg,Brust, Peter,Müller, Christa E.,Wenzel, Barbara
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p. 4650 - 4663
(2018/08/17)
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- PDE9 INHIBITORS WITH IMIDAZO TRIAZINONE BACKBONE AND IMIDAZO PYRAZINONE BACKBONE FOR TREATMENT OF PERIPHERAL DISEASES
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The present invention relates to PDE9 inhibitors and their use for treatment of benign prostate hyperplasia and sickle cell disease.
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Page/Page column 24
(2017/02/09)
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- NEW SUBSTITUTED BIPHENYL ANALOGUES AS DUAL INHIBITORS OF AROMATASE AND SULFATASE
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Provided are new biphenyl derivatives of formula (Ia). These compounds act as aromatase and sulfatase inhibitors. They are particularly useful for treating pathological conditions or diseases in which aromatase and sulfatase are involved. Moreover, provided are processes for the preparation of these compounds and pharmaceutical compositions containing said products and their use for the preparation of a medicament, in particular for the treatment of diseases characterized by aromatase and sulfatase activity such as hormone-dependent cancers.
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Page/Page column 52; 53
(2015/07/16)
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- Aza follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 1: Mitigating the genotoxic liability of an aniline metabolite
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A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.
- Beaulieu, Pierre L.,Bolger, Gordon,Duplessis, Martin,Gagnon, Alexandre,Garneau, Michel,Stammers, Timothy,Kukolj, George,Duan, Jianmin
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p. 1135 - 1139
(2015/02/19)
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- TRIAZOLOPYRAZINE DERIVATIVES
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Compounds of the formula (I) in which R1, R2 and R4 have the meanings indicated in Claim 1, are inhibitors of GCN2, and can be employed, inter alia, for the treatment of cancer.
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Page/Page column 134
(2013/09/26)
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- IP RECEPTOR AGONIST HETEROCYCLIC COMPOUNDS
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The present invention provides heterocyclic derivatives which activate the IP receptor, processes for preparing them, pharmaceutical compositions comprising said derivatives and uses thereof. Activating the IP receptor signaling pathway is useful to treat
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Paragraph 0292; 0293; 0427; 0428
(2013/07/25)
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- Discovery of LAS101057: A potent, selective, and orally efficacious A 2B Adenosine Receptor Antagonist
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The structure-activity relationships for a series of pyrazine-based A 2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identifie
- Eastwood, Paul,Esteve, Cristina,Gonzalez, Jacob,Fonquerna, Silvia,Aiguade, Josep,Carranco, Ines,Domenech, Teresa,Aparici, Monica,Miralpeix, Montserrat,Alberti, Joan,Cordoba, Monica,Fernandez, Raquel,Pont, Merce,Godessart, Nuria,Prats, Neus,Loza, Maria Isabel,Cadavid, Maria Isabel,Nueda, Arsenio,Vidal, Bernat
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scheme or table
p. 213 - 218
(2011/04/26)
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- PYRAZINE DERIVATIVES USEFUL AS ADENOSINE RECEPTOR ANTAGONISTS
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The present invention provides a compound of formula (I) wherein: A represents an optionally substituted monocyclic or polycyclic aryl or heteroaryl group B represents an optionally substituted monocyclic nitrogen-containing heteroaryl group ; and either a) R1 and R2 represent hydrogen or specified substituents, or b) R2, R1 and the -NH- group to which R1 is attached, form a moiety selected from the moiety of formulae (IIa) and (IIb): (IIa) These compounds are useful as antagonists of the A2B receptor, for instance in the treatment of asthma.
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Page/Page column 52-53
(2008/06/13)
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