Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties.
Bioorg Med Chem Lett
; 24(6): 1615-20, 2014 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-24556380
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de Prostaglandina
/
Receptores Imunológicos
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Desenho de Fármacos
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Quinazolinonas
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Amidas
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Isoxazóis
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article