- Development of a Scalable Method for Manufacturing the Central Core of CD73 Inhibitor AB680
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AB680 is a highly potent CD73 small molecule inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Here, we report the development of a scalable and practical method for the manufacturing of the azaindazole central core. This synthesis features an N-oxide formation followed by an α-chlorination with POCl3 leading to the formation of 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine 1 in high yield and 99.5% UV purity. This method was successfully performed on multikilogram scale to support the synthesis of AB680.
- Fournier, Jeremy,Yan, Xuelei,Tran, Anh T.,Grange, Rebecca L.,Jacob, Steven D.,Kalisiak, Jaroslaw,Lawson, Kenneth V.,Connor, Eric F.,Leleti, Manmohan R.,Powers, Jay P.
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p. 157 - 162
(2021/01/09)
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- PARENTERALLY ADMINISTERED IMMUNE ENHANCING DRUGS
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Methods of identifying compounds that modulate the conversion of AMP to adenosine by 5'-nucleotidase, ecto, and that possess particular pharmacokinetic characteristics are described herein. Methods of such compounds, and compositions comprising same, for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, are also provided.
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Paragraph 0280
(2019/10/01)
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- MODULATORS OF 5'-NUCLEOTIDASE, ECTO AND THE USE THEREOF
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Compounds that modulate the conversion of AMP to adenosine by 5'- nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5'-nucleotidase, ecto is also provided.
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Paragraph 0350
(2017/08/01)
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- Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors
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Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.
- Zou, Bin,Chan, Wai Ling,Ding, Mei,Leong, Seh Yong,Nilar, Shahul,Seah, Peck Gee,Liu, Wei,Karuna, Ratna,Blasco, Francesca,Yip, Andy,Chao, Alex,Susila, Agatha,Dong, Hongping,Wang, Qing Yin,Xu, Hao Ying,Chan, Katherine,Wan, Kah Fei,Gu, Feng,Diagana, Thierry T.,Wagner, Trixie,Dix, Ina,Shi, Pei-Yong,Smith, Paul W.
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p. 344 - 348
(2015/03/30)
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