Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10586989 | Bioorganic & Medicinal Chemistry Letters | 2014 | 6 Pages |
Abstract
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
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Authors
Dong Xiao, Xiaohong Zhu, Younong Yu, Ning Shao, Jie Wu, Kevin D. McCormick, Pawan Dhondi, Jun Qin, Robert Mazzola, Haiqun Tang, Ashwin Rao, Phieng Siliphaivanh, Hongchen Qiu, Xiaoxin Yang, Maria Rivelli, Charles G. Garlisi, Steve Eckel,