875781-41-2Relevant articles and documents
Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib
Rozema, Michael J.,Bhagavatula, Lakshmi,Christesen, Alan,Dunn, Travis B.,Ickes, Andrew,Kotecki, Brian J.,Marek, James C.,Moschetta, Eric,Morrill, Westin H.,Mulhern, Mathew,Rasmussen, Michael,Reynolds, Troy,Yu, Su
, p. 949 - 962 (2021/10/21)
Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optimization of the imidazole cyclization, and in-depth understanding of the formation of the urea moiety at the final stage are discussed.
Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ
Bellenie, Benjamin R.,Hall, Edward,Bruce, Ian,Spendiff, Matthew,Culshaw, Andrew,McDonald, Sarah,Ambarkhane, Ameet,Chinn, Colin,Thomas, Matthew,Rosner, Elisabeth,Bracher, Marguerite,Nicklin, Paul,Marshall, Stephen,Coote, Julie,Cullen, Eva,Tessier, Clemence,Wuersch, Kuno,Lal, Ajay,Wallis, Gillian,Hollingworth, Gregory J.,Neef, James
, p. 12304 - 12321 (2021/09/02)
Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγinhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.
Influenza virus replication inhibitors and uses thereof (by machine translation)
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Paragraph 0415; 0417-0420, (2019/10/01)
The invention provides a compound as an influenza virus replication inhibitor, a method for preparing the same, a pharmaceutical composition containing the compound and application. (by machine translation)