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

  • J Med Chem. 2021 Aug 26;64(16):12304-12321. doi: 10.1021/acs.jmedchem.1c00986.
Benjamin R Bellenie  1 ,  Edward Hall  2 ,  Ian Bruce  1 ,  Matthew Spendiff  1 ,  Andrew Culshaw  1 ,  Sarah McDonald  1 ,  Ameet Ambarkhane  1 ,  Colin Chinn  1 ,  Matthew Thomas  1 ,  Elisabeth Rosner  1 ,  Marguerite Bracher  1 ,  Paul Nicklin  1 ,  Stephen Marshall  1 ,  Julie Coote  1 ,  Eva Cullen  1 ,  Clemence Tessier  3 ,  Kuno Wuersch  3 ,  Ajay Lal  2 ,  Gillian Wallis  1 ,  Gregory J Hollingworth  3 ,  James Neef  2
Affiliations
  • 1. Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
  • 2. Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 3. Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
PMID: 34384024 DOI: 10.1021/acs.jmedchem.1c00986
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.

Products