Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ

Abstract

Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.

Designing Small Molecule PI3Kγ Inhibitors: A Review of Structure-Based Methods and Computational Approaches

“…Novartis scientists identified a series of aminopyridine PI3Kγ inhibitors using a novel physiologically relevant in vitro human whole blood neutrophil shape change (hWBSC) assay, in which the inhibitory activity relies on multiple factors, including ontarget potency, cellular permeability, and free fraction in whole blood. 94 The aminopyrazine lead compound 25 showed potent activities in cellular and hWBSC assays (Figure 14B). However, its bioavailability significantly decreased upon dose escalation due to solubility-limited absorption.…”