RESUMO
New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.
Assuntos
Isoquinolinas/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/química , Desenho de Fármacos , Isoxazóis/química , Quinazolinonas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Cães , Meia-Vida , Haplorrinos , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling.
Assuntos
Acetatos/química , Acetatos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Humanos , Pirazóis/síntese química , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
Twenty years have passed since eosinophilic esophagitis was first recognized as a new and distinct entity. Current treatment modalities for eosinophilic esophagitis include the "3 Ds": drugs, allergen avoidance with diet, and esophageal dilation. Drugs entail the limitation that only corticosteroids have a proven efficacy; most other compounds evoke only a minimal effect. Diets must be maintained continuously and they interfere markedly with the quality of life, possibly even involving some risk of malnutrition. A greater understanding of the immunopathogenesis, natural history, and disease spectrum will inevitably lead to improved therapeutic outcomes for this emerging entity.