Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Journal of medicinal chemistry 2012-09, Vol.55 (17), p.7667-7685
Hauptverfasser:	Gonzalez-Lopez de Turiso, Felix, Shin, Youngsook, Brown, Matthew, Cardozo, Mario, Chen, Yi, Fong, David, Hao, Xiaolin, He, Xiao, Henne, Kirk, Hu, Yi-Ling, Johnson, Michael G, Kohn, Todd, Lohman, Julia, McBride, Helen J, McGee, Lawrence R, Medina, Julio C, Metz, Daniela, Miner, Kent, Mohn, Deanna, Pattaropong, Vatee, Seganish, Jennifer, Simard, Jillian L, Wannberg, Sharon, Whittington, Douglas A, Yu, Gang, Cushing, Timothy D
Format:	Artikel
Sprache:	eng
Schlagworte:	Drug Discovery Drug Evaluation, Preclinical Models, Molecular Phosphatidylinositol 3-Kinases - antagonists & inhibitors Protein Kinase Inhibitors - pharmacology
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm300679u