5 research outputs found
Facilitated Chloride Transport Across Phosphatidylcholine Bilayers by an Acyclic Calixarene Derivative: Structure-Function Relationships
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 <b>63</b> was a potent and selective PI3Kβ/δ
dual inhibitor that displayed suitable physicochemical properties
and pharmacokinetic profile for animal studies. Analogue <b>63</b> 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
Discovery and in Vivo Evaluation of (<i>S</i>)‑<i>N</i>‑(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)‑9<i>H</i>‑purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease
The development and optimization
of a series of quinolinylpurines
as potent and selective PI3Kδ kinase inhibitors with excellent
physicochemical properties are described. This medicinal chemistry
effort led to the identification of <b>1</b> (AMG319), a compound
with an IC<sub>50</sub> of 16 nM in a human whole blood assay (HWB),
excellent selectivity over a large panel of protein kinases, and a
high level of in vivo efficacy as measured by two rodent disease models
of inflammation