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Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Xiao D,Zhu X,Yu Y,Shao N,Wu J,McCormick KD,Dhondi P,Qin J,Mazzola R,Tang H,Rao A,Siliphaivanh P,Qiu H,Yang X,Rivelli M,Garlisi CG,Eckel S,Mukhopadhyay G,Correll C,Rindgen D,Aslanian R,Palani A

doi

10.1016/j.bmcl.2014.01.043

subject

Has Abstract

pub_date

2014-03-15 00:00:00

pages

1615-20

issue

6

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(14)00073-0

journal_volume

24

pub_type

杂志文章

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