Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation

A hit-to-lead campaign pursuing the identification of
novel inhalant
small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for
the treatment of inflammatory respiratory diseases is disclosed. A
synthetically versatile pyridazin-3(2H)-one scaffold
was designed, and three exit vectors on the core moiety were used
to explore chemical diversity and optimize pharmacological and absorption,
distribution, metabolism, and excretion (ADME) properties. Desired
modulation of PI3Kδ selectivity and cellular potency as well
as ADME properties in view of administration by inhalation was achieved.
Intratracheal administration of lead compound 26 resulted
in a promising pharmacokinetic profile, thus demonstrating that the
optimization strategy of in vitro profiles successfully
translated to an in vivo setting.