- Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases
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A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.
- Hemmerling, Martin,Nilsson, Stinabritt,Edman, Karl,Eirefelt, Stefan,Russell, Wayne,Hendrickx, Ramon,Johnsson, Eskil,K?rrman M?rdh, Carina,Berger, Markus,Rehwinkel, Hartmut,Abrahamsson, Anna,Dahmén, Jan,Eriksson, Anders R.,Gabos, Balint,Henriksson, Krister,Hossain, Nafizal,Ivanova, Svetlana,Jansson, Anne-Helene,Jensen, Tina J.,Jerre, Anders,Johansson, Henrik,Klingstedt, Tomas,Lepist?, Matti,Lindsj?, Martin,Mile, Irene,Nikitidis, Grigorios,Steele, John,Tehler, Ulrika,Wissler, Lisa,Hansson, Thomas
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p. 8591 - 8605
(2017/11/03)
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- Self-assembled asymmetric catalyst engaged in a continuous-flow platform: An anti -selective catalytic asymmetric nitroaldol reaction
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An anti-selective catalytic asymmetric nitroaldol reaction was manifested in a continuous-flow platform. The requisite Nd/Na heterogeneous catalyst was readily prepared by self-assembly of an amide-based chiral ligand, NdO 1/5(OiPr)13/5, NaHMDS, and a multiwalled carbon nanotube without covalent linkage. A stainless-steel column filled with the Nd/Na catalyst was incorporated in a flow system to promote the nitroaldol reaction with high stereoselectivity. The flow system with the heterogeneous catalyst obviated the quenching operation, and the cooling system was minimized.
- Hashimoto, Kazuki,Kumagai, Naoya,Shibasaki, Masakatsu
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supporting information
p. 3496 - 3499
(2014/07/21)
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- CRYSTALLINE FORM OF INDAZOLYL AMIDE DERIVATIVES FOR THE TREATMENT GLUCOCORTICOID RECEPTOR MEDIATED DISORDERS
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Crystalline forms of 2,2,2-trifluoro-N-[(lR,2S)-l-[l-(4-fluorophenyl)in- dazol-5-yl]oxy-l-(3-methoxyphenyl)propan-2-yl]acetamide, processes for obtaining them, pharmaceutical intermediates used in their manu? facture, pharmaceutical compositions containing them, and their use in medical treatment.
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Page/Page column 41-42
(2013/03/26)
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