Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease.
J Med Chem
; 62(9): 4312-4324, 2019 05 09.
Article
em En
| MEDLINE
| ID: mdl-30869888
ABSTRACT
5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Doença da Artéria Coronariana
/
Inibidores da Proteína Ativadora de 5-Lipoxigenase
Limite:
Animals
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Female
/
Humans
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Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article