- 1-PYRAZOLYL, 5-, 6- DISUBSTITUTED INDAZOLE DERIVATIVES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
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The present invention is directed to substituted certain 1-pyrazolyl, 5-, 6- disubstituted indazole derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2, and ring A are as defined herein, which are potent inhibitors of LRRK2 kinase and may be useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease and other diseases and disorders described herein. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of diseases, such as Parkinson's disease, in which LRRK-2 kinase is involved.
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Page/Page column 53; 54
(2020/12/29)
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- Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action
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Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease.
- Selakovi?, ?ivota,Tran, Julie P.,Kota, Krishna P.,Lazi?, Marija,Retterer, Cary,Besh, Robert,Panchal, Rekha G.,Soloveva, Veronica,Sean, Vantongreen A.,Jay, Wells B.,Pavi?, Aleksandar,Verbi?, Tatjana,Vasiljevi?, Branka,Kuehl, Kathleen,Duplantier, Allen J.,Bavari, Sina,Mudhasani, Rajini,?olaja, Bogdan A.
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supporting information
p. 32 - 50
(2018/11/21)
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- Manganese salen complexes with acid-base catalytic auxiliary: Functional mimetics of catalase
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Antioxidant therapies have been considered for a wide variety of disorders associated with oxidative stress, and synthetic catalytic scavengers of reactive oxygen species would be clinically superior to stoichiometric ones. Among them, salen-manganese complexes (Mn(Salen)) seem promising, because they exhibit dual functions, i.e. superoxide dismutase- and catalase-mimetic activities. We have been developing enzyme-mimetic Mn(Salen) complexes bearing a functional group that enhances their catalytic activity. Here, we describe the design and synthesis of novel Mn(Salen) complexes with general acid-base catalytic functionality, inspired by the reaction mechanism of catalase. As expected, these Mn(Salen) complexes showed superior catalase-like activity and selectivity, while retaining moderate SOD-like activity. An unsubstituted pyridyl group worked well as a functionality to promote catalase-like activity. The introduced functionality did not alter the redox potential suggesting that the auxiliary-modified complex acted as an acid-base catalyst analogous to catalase. We believe that our approach provides a new design principle for sophisticated catalyst design. Further, the compounds described here appear to be good candidates for use in antioxidant therapy.
- Noritake, Yukinobu,Umezawa, Naoki,Kato, Nobuki,Higuchi, Tsunehiko
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p. 3653 - 3662
(2013/05/09)
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- Novel multifunctional organic semiconductor materials based on 4,8-substituted 1,5-naphthyridine: Synthesis, single crystal structures, opto-electrical properties and quantum chemistry calculation
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A series of 4,8-substituted 1,5-naphthyridines (1a-1h) have been successfully synthesised by a Suzuki cross-coupling between 4,8-dibromo-1,5- naphthyridine (4) and the corresponding boronic acids (2a-2h) in the presence of catalytic palladium acetate in yields of 41.4-75.8% and have ben well characterized. They are thermally robust with high phase transition temperatures (above 186 °C). Compounds 1b, 1e and 1f crystallized in the monoclinic crystal system with the space groups P21/c, P21/c and P21/n, respectively. All of them show the lowest energy absorption bands (λmaxAbs: 294-320 nm), revealing low optical band gaps (2.77-3.79 eV). These materials emit blue fluorescence with λmaxEm ranging from 434-521 nm in dilute solution in dichloromethane and 400-501 nm in the solid state. 4,8-Substituted 1,5-naphthyridines 1a-1h have estimated electron affinities (EA) of (2.38-2.72 eV) suitable for electron-transport materials and ionization potentials (IP) of 4.85-5.04 eV facilitate excellent hole-injecting/hole-transport materials properties. Quantum chemical calculations using DFT B3LYP/6-31G* showed nearly identical the lowest unoccupied molecular orbitals (LUMO) of -2.39 to -2.19 eV and the highest occupied molecular orbitals (HOMO) of -5.33 to -6.84 eV. These results demonstrate the 4,8-substituted 1,5-naphthyridines 1a-1h with a simple architecture might be promising blue-emitting (or blue-green-emitting) materials, electron-transport materials and hole-injecting/hole-transport materials for applications for developing high-efficiency OLEDs.
- Wang, Kun-Yan,Chen, Chen,Liu, Jin-Fang,Wang, Qin,Chang, Jin,Zhu, Hong-Jun,Li, Chong
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scheme or table
p. 6693 - 6704
(2012/09/22)
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- [4[4-(5-AMINOMETHYL-2-FLUORO-PHENYL)-PIPERIDIN-1-YL]-(1H-PYRROLO-PYRIDIN-YL)-METHANONES AND SYNTHESIS THEREOF
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The present invention relates herein to compounds and compositions for the treatment and amelioration of inflammatory disease. Specifically the present invention relates to compounds that having a tryptase inhibition activity and the intermediates thereof, pharmaceutical compositions comprising such compounds, and a method of treating subjects suffering from a condition disease or disorder that can be ameliorated by the administration of an inhibitor of tryptase including but not limited to for example asthma and other inflammatory diseases including age-related macular degeneration.
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Page/Page column 62
(2011/07/09)
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- Development of an efficient and scalable process of a respiratory syncytial virus inhibitor
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An improved process has been developed for compound 1, a respiratory syncytial virus (RSV) inhibitor. This improved process is convergent, safe, efficient, and useful to prepare compound 1 in kilogram quantities.
- Provencal, David P.,Gesenberg, Kirsten D.,Wang, Hua,Escobar, Carlos,Wong, Henry,Brown, Matthew A.,Staab, Andrew J.,Pendri, Yadagiri R.
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p. 903 - 908
(2013/09/03)
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- Comparison of the effects of 5- and 6-HOAt on model peptide coupling reactions relative to the cases for the 4- and 7-isomers
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(equation presented) Synthesis of 5- and 6-HOAt has completed the full set of the four HOAt isomers derived from HOBt by insertion of a single nitrogen atom in the benzenoid nucleus. Comparison of the reactivity of all four isomers in model peptide coupling reactions has confirmed the unique character of the 7-isomer in promoting selectivity and maintaining configuration at the reactive carboxylic acid residue.
- Carpino, Louis A.,Imazumi, Hideko,Foxman, Bruce M.,Vela, Michael J.,Henklein, Peter,El-Faham, Ayman,Klose, Jana,Bienert, Michael
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p. 2253 - 2256
(2007/10/03)
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- Cross coupling strategies towards the synthesis of the streptonigrin CD moiety
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An efficient route to an appropriate model of the streptonigrin 4- phenylpyridine CD moiety is reported. 4-Chloro-3-nitropyridine was found to be the key precursor and its reactivity in cross coupling reactions was further investigated.
- Crous, Renier,Dwyer, Catherine,Holzapfel, Cedric W.
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p. 721 - 726
(2007/10/03)
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